Cancer Research and Treatment

Original Articles

ALYREF-Mediated Regulation of TBL1XR1 and KMT2E Synergistically Upregulates APOC1, Contributing to Oxaliplatin Resistance in Esophageal Cancer: Jie Hu, Qilong Liu, Bi Feng, Yanling Lu, Kai Chen; Received November 15, 2024 Accepted February 3, 2025 Published online February 4, 2025; DOI: https://doi.org/10.4143/crt.2024.1091 [Accepted]

Abstract PDF: Purpose
Esophageal cancer (EC) is a rapidly progressing malignancy characterized by a low survival rate and limited treatment success, largely due to late-stage detection, frequent recurrence, and a high propensity for metastasis, despite ongoing advances in therapeutic strategies. While oxaliplatin (L-OHP) is a potent chemotherapeutic agent that induces apoptosis in EC cells, its effectiveness is significantly hindered by the development of resistance.
Materials and Methods
The assessment of gene and protein expression was conducted through a combination of RT-qPCR, Western blot, and IHC staining. Cell viability was assessed using the CCK-8 assay. The interactions among ALYREF, TBL1XR1, KMT2E, and APOC1 were investigated through RIP, ChIP, ChIP-reChIP, RNA pulldown, and dual-luciferase assays. An in vivo mouse model of EC was established.
Results
Expression levels of both APOC1 and ALYREF were elevated in L-OHP-resistant EC tissues and cell lines, and their silencing enhanced sensitivity to L-OHP. TBL1XR1 and KMT2E synergistically upregulated APOC1 expression. Moreover, ALYREF recognized the m5C sites on TBL1XR1 and KMT2E mRNAs, stabilizing these transcripts and promoting APOC1 expression. The regulatory role of these interactions was further validated in vivo.
Conclusion
This study demonstrated that ALYREF interacted with the m5C sites on TBL1XR1 and KMT2E mRNAs, enhancing their stability and leading to increased transcription of APOC1, which in turn contributed to L-OHP resistance in EC. These findings suggest that targeting APOC1 could be a promising strategy for overcoming L-OHP resistance in EC.

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Breast cancer

Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer after Trastuzumab Failure (PROVE): A Prospective Phase 2 Study: Chunfang Hao, Xu Wang, Yehui Shi, Zhongsheng Tong, Shufen Li, Xiaodong Liu, Lan Zhang, Jie Zhang, Wenjing Meng, Li Zhang; Cancer Res Treat. 2025;57(2):434-442. Published online August 9, 2024; DOI: https://doi.org/10.4143/crt.2024.340

Abstract PDF PubReader ePub

Purpose
Approximately 50%-74% of patients with metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients.
Materials and Methods
In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400 mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.
Results
From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cutoff date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% confidence interval [CI], 8.3 to 18.5). With all patients evaluated, an ORR of 38.9% (95% CI, 23.1 to 56.5) and a DCR of 83.3% (95% CI, 67.2 to 93.6) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs.
Conclusion
Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

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Adjuvant Metronomic Chemotherapy After Surgery in pT1-T2 N0 M0 HER2-Positive and ER/PR-Positive Breast Cancer Plus Targeted Therapy, Anti-Hormonal Therapy, and Radiotherapy, with or Without Immunotherapy: A New Operational Proposal
Luca Roncati
Cancers.2025; 17(8): 1323. CrossRef

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Genitourinary cancer

Oncological Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide with versus without Confirmatory Bone Scan: Chang Wook Jeong, Jang Hee Han, Dong Deuk Kwon, Jae Young Joung, Choung-Soo Kim, Hanjong Ahn, Jun Hyuk Hong, Tae-Hwan Kim, Byung Ha Chung, Seong Soo Jeon, Minyong Kang, Sung Kyu Hong, Tae Young Jung, Sung Woo Park, Seok Joong Yun, Ji Yeol Lee, Seung Hwan Lee, Seok Ho Kang, Cheol Kwak; Cancer Res Treat. 2024;56(2):634-641. Published online December 5, 2023; DOI: https://doi.org/10.4143/crt.2023.848

Abstract PDF Supplementary Material PubReader ePub

Purpose
In men with metastatic castration-resistant prostate cancer (mCRPC), new bone lesions are sometimes not properly categorized through a confirmatory bone scan, and clinical significance of the test itself remains unclear. This study aimed to demonstrate the performance rate of confirmatory bone scans in a real-world setting and their prognostic impact in enzalutamide-treated mCRPC.
Materials and Methods
Patients who received oral enzalutamide for mCRPC during 2014-2017 at 14 tertiary centers in Korea were included. Patients lacking imaging assessment data or insufficient drug exposure were excluded. The primary outcome was overall survival (OS). Secondary outcomes included performance rate of confirmatory bone scans in a real-world setting. Kaplan-Meier analysis and multivariate Cox regression analysis were performed.
Results
Overall, 520 patients with mCRPC were enrolled (240 [26.2%] chemotherapy-naïve and 280 [53.2%] after chemotherapy). Among 352 responders, 92 patients (26.1%) showed new bone lesions in their early bone scan. Confirmatory bone scan was performed in 41 patients (44.6%), and it was associated with prolonged OS in the entire population (median, 30.9 vs. 19.7 months; p < 0.001), as well as in the chemotherapy-naïve (median, 47.2 vs. 20.5 months; p=0.011) and post-chemotherapy sub-groups (median, 25.5 vs. 18.0 months; p=0.006). Multivariate Cox regression showed that confirmatory bone scan performance was an independent prognostic factor for OS (hazard ratio 0.35, 95% confidence interval, 0.18 to 0.69; p=0.002).
Conclusion
Confirmatory bone scan performance was associated with prolonged OS. Thus, the premature discontinuation of enzalutamide without confirmatory bone scans should be discouraged.

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ECM-mimicking hydrogel models of human adipose tissue identify deregulated lipid metabolism in the prostate cancer-adipocyte crosstalk under antiandrogen therapy
Agathe Bessot, Joan Röhl, Maria Emmerich, Anton Klotz, Akhilandeshwari Ravichandran, Christoph Meinert, David Waugh, Jacqui McGovern, Jenni Gunter, Nathalie Bock
Materials Today Bio.2025; 30: 101424. CrossRef

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Lung and Thoracic cancer

Targeting CD73 to Overcomes Resistance to First-Generation EGFR Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer: Miso Kim, Soyeon Kim, Jeemin Yim, Bhumsuk Keam, Tae Min Kim, Yoon Kyung Jeon, Dong-Wan Kim, Dae Seog Heo; Cancer Res Treat. 2023;55(4):1134-1143. Published online May 23, 2023; DOI: https://doi.org/10.4143/crt.2023.311

Abstract PDF Supplementary Material PubReader ePub

Purpose
In patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs) improve response rate and survival. However, most patients eventually develop resistance. This study aimed to identify the role of CD73 in EGFR-mutant NSCLC and explore whether CD73 inhibition may serve as a therapeutic strategy in NSCLC patients with acquired resistance to EGFR-TKIs.
Materials and Methods
We evaluated the prognostic role of CD73 expression in EGFR-mutant NSCLC using tumor samples from a single institution. We silenced CD73 in EGFR-TKI–resistant cell lines using short hairpin RNA (shRNA) targeting CD73 and also transfected a vector alone as a negative control. Using these cell lines, cell proliferation and viability assays, immunoblot assays, cell cycle analysis, colony-forming assays, flow cytometry, and apoptosis analysis were performed.
Results
High expression of CD73 was associated with shorter survival in patients with metastatic EGFR-mutant NSCLC treated with first-generation EGFR-TKI. CD73 inhibition synergistically inhibited cell viability with first-generation EGFR-TKI treatment compared with the negative control. When CD73 inhibition and EGFR-TKI treatment were combined, G0/G1 cell cycle arrest was induced through the regulation of p21 and cyclin D1. In addition, the apoptosis rate was increased in CD73 shRNA-transfected cells treated with EGFR-TKI.
Conclusion
High expression of CD73 adversely affects the survival of patients with EGFR-mutant NSCLC. The study demonstrated that inhibiting CD73 in EGFR-TKI–resistant cell lines resulted in increased apoptosis and cell cycle arrest, which overcame the acquired resistance to first-generation EGFR-TKIs. Further research is needed to determine whether blocking CD73 plays a therapeutic role in EGFR-TKI–resistant patients with EGFR-mutant NSCLC.

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Review Article

Cellular Dormancy in Cancer: Mechanisms and Potential Targeting Strategies: Hye-Young Min, Ho-Young Lee; Cancer Res Treat. 2023;55(3):720-736. Published online March 22, 2023; DOI: https://doi.org/10.4143/crt.2023.468

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Cancer is a leading cause of disease-related mortality worldwide. Drug resistance is one of the primary reasons for the failure of anticancer therapy. There are a number of underlying mechanisms for anticancer drug resistance including genetic/epigenetic modifications, microenvironmental factors, and tumor heterogeneity. In the present scenario, researchers have focused on these novel mechanisms and strategies to tackle them. Recently, researchers have recognized the ability of cancer to become dormant because of anticancer drug resistance, tumor relapse, and progression. Currently, cancer dormancy is classified into “tumor mass dormancy” and “cellular dormancy.” Tumor mass dormancy represents the equilibrium between cell proliferation and cell death under the control of blood supply and immune responses. Cellular dormancy denotes the state in which cells undergo quiescence and is characterized by autophagy, stress-tolerance signaling, microenvironmental cues, and epigenetic modifications. Cancer dormancy has been regarded as the stem of primary or distal recurrent tumor formation and poor clinical outcomes in cancer patients. Despite the insufficiency of reliable models of cellular dormancy, the mechanisms underlying the regulation of cellular dormancy have been clarified in numerous studies. A better understanding of the biology of cancer dormancy is critical for the development of effective anticancer therapeutic strategies. In this review, we summarize the characteristics and regulatory mechanisms of cellular dormancy, introduce several potential strategies for targeting cellular dormancy, and discuss future perspectives.

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Original Article

Gastrointestinal cancer

Trastuzumab Combined with Irinotecan in Patients with HER2-Positive Metastatic Colorectal Cancer: A Phase II Single-Arm Study and Exploratory Biomarker Analysis: Ting Xu, Xicheng Wang, Ying Xin, Zhenghang Wang, Jifang Gong, Xiaotian Zhang, Yanyan Li, Congcong Ji, Yu Sun, Feilong Zhao, Depei Huang, Yuezong Bai, Jian Li, Lin Shen; Cancer Res Treat. 2023;55(2):626-635. Published online December 23, 2022; DOI: https://doi.org/10.4143/crt.2022.1058

Abstract PDF Supplementary Material PubReader ePub

Purpose
The human epidermal growth factor receptor 2 (HER2) is an established therapeutic target for various kinds of solid tumors. HER2 amplification occurs in approximately 1% to 6% of colorectal cancer. In this study, we aimed to assess the efficacy and safety of trastuzumab in combination with chemotherapy in HER2-positive metastatic colorectal cancer (mCRC).
Materials and Methods
An open-label, phase II trial (Clinicaltrials.gov: NCT03185988) was designed to evaluate the antitumor activity of trastuzumab and chemotherapy in HER2-positive digestive cancers excluding gastric cancer in 2017. Patients from this trial with HER2-positive, KRAS/BRAF wild-type, unresectable mCRC were analyzed in this manuscript. Eligible patients were treated with trastuzumab (8 mg/kg loading dose and then 6 mg/kg every 3 weeks) and irinotecan (120 mg/m² days 1 and 8 every 3 weeks). The primary endpoint was the objective response rate.
Results
Twenty-one HER2-positive mCRC patients were enrolled in this study. Seven patients (33.3%) achieved an objective res-ponse, and 11 patients (52.4%) had stable disease as their best response. The median progression-free survival (PFS) was 4.3 months (95% confidence interval, 2.7 to 5.9). Four of the 21 patients (19.0%) had grade 3 adverse events, including leukopenia, neutropenia, urinary tract infection, and diarrhea. No treatment-related death was reported. Exploratory analyses revealed that high tumor tissue HER2 copy number was associated with better therapeutic response and PFS. Alterations in the mitogen-activated protein kinase pathway, HER2 gene, phosphoinositide 3-kinase/AKT pathway, and cell cycle control genes were potential drivers of trastuzumab resistance in mCRC.
Conclusion
Trastuzumab combined with chemotherapy is a potentially effective and well-tolerated therapeutic regimen in mCRC with a high HER2 copy number.

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Yeliz Benli, Helin Arıkan, Özge Akbulut-Çalışkan
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Mehrshad Ebrahimpour, Hamidreza Hosseinzadeh, Farshad Abedi, Mohammad Moeini Nodeh, Abolghasem Allahyari, Amirhossein Sahebkar, Omid Arasteh
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Review Article

Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer: Joel Rivera-Concepcion, Dipesh Uprety, Alex A. Adjei; Cancer Res Treat. 2022;54(2):315-329. Published online February 18, 2022; DOI: https://doi.org/10.4143/crt.2022.078

Abstract PDF PubReader ePub

Precision oncology has fundamentally changed how we diagnose and treat cancer. In recent years, there has been a significant change in the management of patients with oncogene-addicted advanced-stage NSCLC. Increasing amounts of identifiable oncogene drivers have led to the development of molecularly targeted drugs. Undoubtedly, the future of thoracic oncology is shifting toward increased molecular testing and the use of targeted therapies. For the most part, these novel drugs have proven to be safe and effective. As with all great innovations, targeted therapies pose unique challenges. Drug toxicities, resistance, access, and costs are some of the expected obstacles that will need to be addressed. This review highlights some of the major challenges in the use of targeted therapies in NSCLC and provides guidance for the future strategies.

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Original Articles

Sarcoma

Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma: Zhengbo Hu, Lugen Li, Wenxing Lan, Xiao Wei, Xiangyuan Wen, Penghuan Wu, Xianliao Zhang, Xinhua Xi, Yufa Li, Liqi Wu, Wenhu Li, Xiaohong Liao; Cancer Res Treat. 2022;54(1):277-293. Published online May 11, 2021; DOI: https://doi.org/10.4143/crt.2021.320

Abstract PDF PubReader ePub

Purpose
Osteosarcoma (OS) universally exhibits heterogeneity and cisplatin (CDDP) resistance. Although the Wee1/CDC2 and nuclear factor кB (NF-κB) pathways were reported to show abnormal activation in some tumor cells with CDDP resistance, whether there is any concrete connection is currently unclear. We explored it in human OS cells.
Materials and Methods
Multiple OS cell lines were exposed to a Wee1 inhibitor (AZD1775) and CDDP to assess the half-maximal inhibitory concentration values. Western blot, coimmunoprecipitation, confocal immunofluorescence, cell cycle, and Cell Counting Kit-8assays were performed to explore the connection between the Wee1/CDC2 and NF-κB pathways and their subsequent physiological contribution to CDDP resistance. Finally, CDDP-resistant PDX-OS xenograft models were established to confirm that AZD1775 restores the antitumor effects of CDDP.
Results
A sensitivity hierarchy of OS cells to CDDP and AZD1775 exists. In the highly CDDP-tolerant cell lines, Wee1 and RelA were physically crosslinked, which resulted in increased abundance of phosphorylated CDC2 (Y15) and RelA (S536) and consequent modulation of cell cycle progression, survival, and proliferation. Wee1 inhibition restored the effects of CDDP on these processes in CDDP-resistant OS cells. In addition, animal experiments with CDDP-resistant PDX-OS cells showed that AZD1775 combined with CDDP not only restored CDDP efficacy but also amplified AZD1775 in inhibiting tumor growth and prolonged the median survival of the mice.
Conclusion
Simultaneous enrichment of molecules in the Wee1/CDC2 and NF-κB pathways and their consequent coactivation is a new molecular mechanism of CDDP resistance in OS cells. OS with this molecular signature may respond well to Wee1 inhibition as an alternative treatment strategy.

Citations

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Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1
Qi Li, Wenjie Yang, Qingyi Zhang, Daoming Zhang, Jun Deng, Binxin Chen, Ping Li, Huanqi Zhang, Yiming Jiang, Yangling Li, Bo Zhang, Nengming Lin
Cancer Cell International.2024;[Epub] CrossRef
BRK confers tamoxifen-resistance in breast cancer via regulation of tyrosine phosphorylation of CDK1
Aditya Mandapati, Zhibin Ning, Akanksha Baharani, Kiven Erique Lukong
Cellular Signalling.2023; 108: 110723. CrossRef
Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process
Yu-Li Su, Ling-Yi Xiao, Shih-Yu Huang, Chia-Che Wu, Li-Chung Chang, Yi-Hua Chen, Hao-Lun Luo, Chun-Chieh Huang, Ting-Ting Liu, Jei-Ming Peng
Cells.2023; 12(11): 1471. CrossRef
Network pharmacology-based research on the effect of angelicin on osteosarcoma and the underlying mechanism
Yafang Zhang, Junqiang Wei, Lingwei Kong, Mingze Song, Yange Zhang, Xiangyu Xiao, Haiying Cao, Zhehong Li, Ning Yang, Yu Jin
Aging.2023;[Epub] CrossRef
Identification of Cell Subpopulations and Interactive Signaling Pathways From a Single-Cell RNA Sequencing Dataset in Osteosarcoma: A Comprehensive Bioinformatics Analysis
Rong Wu, Xiaojie Dou, Haidong Li, Zhenguo Sun, Heng Li, Yuxin Shen, Wei Weng, Jikang Min
Frontiers in Oncology.2022;[Epub] CrossRef
MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity
Negin Soghli, Gordon A. Ferns, Fatemeh Sadeghsoltani, Durdi Qujeq, Tooba Yousefi, Mostafa Vaghari-Tabari
Biochemical Pharmacology.2022; 201: 115094. CrossRef
Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers
Zhengbo Hu, Ramya Viswanathan, Hui Cheng, Jianghong Chen, Xinping Yang, Angel Huynh, Paul Clavijo, Yi An, Yvette Robbins, Christopher Silvin, Clint Allen, Pinar Ormanoglu, Scott Martin, Shaleeka Cornelius, Anthony Saleh, Zhong Chen, Carter Van Waes, Ethan
Molecular Cancer Research.2022; 20(6): 867. CrossRef
Epithelial to Mesenchymal Transition Relevant Subtypes with Distinct Prognosis and Responses to Chemo- or Immunotherapies in Osteosarcoma
Yang Zhou, Gai Li, Hu Li, Fuchong Lai, Pingguo Duan, Ming Cheng, Fu Wang
Journal of Immunology Research.2022; 2022: 1. CrossRef
Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment
Cassidy M. Van Stiphout, Anita K. Luu, Alicia M. Viloria-Petit
Cancers.2022; 14(19): 4544. CrossRef

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9 Crossref

Lung and Thoracic cancer

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer: Chaelin Lee, Miso Kim, Dong-Wan Kim, Tae Min Kim, Soyeon Kim, Sun-Wha Im, Yoon Kyung Jeon, Bhumsuk Keam, Ja-Lok Ku, Dae Seog Heo; Cancer Res Treat. 2022;54(1):140-149. Published online May 3, 2021; DOI: https://doi.org/10.4143/crt.2021.385

Abstract PDF Supplementary Material PubReader ePub

Purpose
Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.
Materials and Methods
We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDD^WT), EGFR-KDD domain 1 T790M (EGFR-KDD^D1T), EGFR-KDD domain 2 T790M (EGFR-KDD^D2T), and EGFR-KDD both domain T790M (EGFR-KDD^BDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.
Results
In cell viability assays, SNU-4784 cells and EGFR-KDD^WT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDD^T790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDD^BDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDD^T/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.
Conclusion
Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDD^T790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

Citations

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Colorectal cancer harboring EGFR kinase domain duplication response to EGFR tyrosine kinase inhibitors
Tomohiro Kondo, Osamu Kikuchi, Yoshihiro Yamamoto, Tomohiko Sunami, Yafeng Wang, Keita Fukuyama, Tomoki Saito, Hideto Nakahara, Sachiko Minamiguchi, Masashi Kanai, Atsushi Sueyoshi, Manabu Muto
The Oncologist.2025;[Epub] CrossRef
A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology
Justin J. Kim, Ilse K. Schaeffner, David E. Heppner, Ciric To, Pasi A. Jänne, Tyler S. Beyett, Michael J. Eck
Molecular Pharmacology.2024; 105(2): 97. CrossRef
Tumor-associated Macrophages Mediate Gefitinib Resistance in Lung Cancer through HGF/c-met Signaling Pathway
Xiali Tang, Yu Chen, Demin Jiao, Xiang Liu, Jun Chen, Yongyang Liu, Chunyan Jiang, Qingyong Chen
Anti-Cancer Agents in Medicinal Chemistry.2024; 24(1): 30. CrossRef
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Ziyang Jiang, Zhihan Gu, Xiaomin Yu, Tao Cheng, Bofu Liu
Frontiers in Oncology.2024;[Epub] CrossRef
Molecular Targets and Mechanisms of Casein-Derived Tripeptides Ile-Pro-Pro and Val-Pro-Pro on Hepatic Glucose Metabolism
Chenyang Wang, Lin Zheng, Mouming Zhao
Journal of Agricultural and Food Chemistry.2023; 71(48): 18802. CrossRef
Erlotinib

Reactions Weekly.2022; 1907(1): 208. CrossRef

9,554 View
340 Download
5 Web of Science
6 Crossref

Gynecologic cancer

A Preoperative Nomogram for Predicting Chemoresistance to Neoadjuvant Chemotherapy in Patients with Locally Advanced Cervical Squamous Carcinoma Treated with Radical Hysterectomy: Zhengjie Ou, Dan Zhao, Bin Li, Yating Wang, Shuanghuan Liu, Yanan Zhang; Cancer Res Treat. 2021;53(1):233-242. Published online September 14, 2020; DOI: https://doi.org/10.4143/crt.2020.159

Abstract PDF PubReader ePub

Purpose
This study aimed to investigate the factors associated with chemoresistance to neoadjuvant chemotherapy (NACT) followed by radical hysterectomy (RH) and construct a nomogram to predict the chemoresistance in patients with locally advanced cervical squamous carcinoma (LACSC).
Materials and Methods
This retrospective study included 516 patients with International Federation of Gynecology and Obstetrics (2003) stage IB2 and IIA2 cervical cancer treated with NACT and RH between 2007 and 2017. Clinicopathologic data were collected, and patients were assigned to training (n=381) and validation (n=135) sets. Univariate and multivariate analyses were performed to analyze factors associated with chemoresistance to NACT. A nomogram was built using the multivariate logistic regression analysis results. We evaluated the discriminative ability and accuracy of the model using a concordance index and a calibration curve. The predictive probability of chemoresistance to NACT was defined as > 34%.
Results
Multivariate analysis confirmed menopausal status, clinical tumor diameter, serum squamous cell carcinoma antigen level, and parametrial invasion on magnetic resonance imaging before treatment as independent prognostic factors associated with chemoresistance to NACT. The concordance indices of the nomogram for training and validation sets were 0.861 (95% confidence interval [CI], 0.822 to 0.900) and 0.807 (95% CI, 0.807 to 0.888), respectively. Calibration plots revealed a good fit between the modelpredicted probabilities and actual probabilities (Hosmer-Lemeshow test, p=0.597). Furthermore, grouping based on the nomogram was associated with progression-free survival.
Conclusion
We developed a nomogram for predicting chemoresistance in LACSC patients treated with RH. This nomogram can help physicians make clinical decisions regarding primary management and postoperative follow-up of the patients.

Citations

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Neoadjuvant chemotherapy with carboplatin and paclitaxel in pregnant women with advanced stage cervical cancer: Maternal and perinatal outcomes
Bruna Elias Parreira Lopes Ferraz, Roney César Signorini Filho, Lucas Ribeiro Borges Carvalho, Michelle Samora Almeida, Tatiana Carvalho de Souza Bonetti, Edward Araujo Júnior, Antonio Braga, Sue Yazaki Sun
Journal of Gynecology Obstetrics and Human Reproduction.2025; 54(2): 102890. CrossRef
Are biomarkers expression and clinical-pathological factors predictive markers of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer?
Antonino Ditto, Mariangela Longo, Giulia Chiarello, Luigi Mariani, Biagio Paolini, Umberto Leone Roberti Maggiore, Fabio Martinelli, Giorgio Bogani, Francesco Raspagliesi
European Journal of Surgical Oncology.2024; 50(6): 108311. CrossRef
A Deep Learning Radiomics Nomogram to Predict Response to Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer: A Two-Center Study
Yajiao Zhang, Chao Wu, Zhibo Xiao, Furong Lv, Yanbing Liu
Diagnostics.2023; 13(6): 1073. CrossRef
Machine Learning-Assisted Ensemble Analysis for the Prediction of Response to Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer
Yibao Huang, Qingqing Zhu, Liru Xue, Xiaoran Zhu, Yingying Chen, Mingfu Wu
Frontiers in Oncology.2022;[Epub] CrossRef

6,079 View
127 Download
5 Web of Science
4 Crossref

Long Non-coding RNA CCAT1 Sponges miR-454 to Promote Chemoresistance of Ovarian Cancer Cells to Cisplatin by Regulation of Surviving: De-Ying Wang, Na Li, Yu-Lan Cui; Cancer Res Treat. 2020;52(3):798-814. Published online March 3, 2020; DOI: https://doi.org/10.4143/crt.2019.498

Abstract PDF Supplementary Material PubReader ePub

Purpose
Colon cancer-associated transcript 1 (CCAT1) was identified as an oncogenic long non-coding RNA (lncRNA) in a variety of cancers. However, there was a lack of understanding of the mechanism by which CCAT1 conferred cisplatin (also known as DDP) resistance in ovarian cancer cells.
Materials and Methods
Cell viability of A2780, SKOV3, A2780/DDP, and SKOV3/DDP cells upon cisplatin treatment was monitored by MTT assay. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected the expression levels of CCAT1 and miR-454. The effect of sh-CCAT1 on cisplatin response was investigated in xenografts study. Bioinformatic analysis, luciferase reporter assay and qRT-PCR were conducted to validate the direct interaction among CCAT1, miR-454, and survivin. Apoptosis was determined by flow cytometry after dual staining of Annexin-V-FITC/propidium iodide, and the expression of apoptosis-related proteins Bcl-2, Bax and survivin were detected by qRT-PCR and Western blotting. Xenograft study was conducted to monitor in vivo tumor formation.
Results
CCAT1 was highly expressed in cisplatin-resistant ovarian cancer cell line A2780/DDP and SKOV3/DDP. Knockdown of CCAT1 restored sensitivity to cisplatin in vitro and in vivo. Our data revealed that silencing of CCAT1 promoted cisplatin-induced apoptosis via modulating the expression of pro- or anti-apoptotic proteins Bax, Bcl-2, and survivin. CCAT1 directly interacted with miR-454, and miR-454 overexpression potentiated cisplatin-induced apoptosis. Survivin was identified as a functional target of miR-454, restoration of survivin attenuated the effect of miR-454 on cisplatin response. In addition, miR-454 inhibitor or overexpression of survivin was found to abolish sh-CCAT1–induced apoptosis upon cisplatin treatment.
Conclusion
CCAT1/miR-454/survivin axis conferred cisplatin resistance in ovarian cancer cells.

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CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer: Guolin Zhang, Xin Luo, Wei Zhang, Engeng Chen, Jianbin Xu, Fei Wang, Gaoyang Cao, Zhenyu Ju, Dongai Jin, Xuefeng Huang, Wei Zhou, Zhangfa Song; Cancer Res Treat. 2020;52(2):622-633. Published online December 31, 2019; DOI: https://doi.org/10.4143/crt.2019.593

Abstract PDF PubReader ePub

Purpose
5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu.
Materials and Methods
CXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells.
Results
In this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13.
Conclusion
These results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatment strategies.

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Alterations in PD-L1 Expression Associated with Acquisition of Resistance to ALK Inhibitors in ALK-Rearranged Lung Cancer: Su-Jung Kim, Soyeon Kim, Dong-Wan Kim, Miso Kim, Bhumsuk Keam, Tae Min Kim, Yusoo Lee, Jaemoon Koh, Yoon Kyung Jeon, Dae Seog Heo; Cancer Res Treat. 2019;51(3):1231-1240. Published online December 31, 2018; DOI: https://doi.org/10.4143/crt.2018.486

Abstract PDF Supplementary Material PubReader ePub

Purpose
The purpose of this study was to evaluate the relationships between the resistance of anaplastic lymphoma kinase (ALK)‒positive non-small cell lung cancer (NSCLC) to ALK inhibitors and the programmed cell death-1/programmed cell death–ligand 1 (PD-L1) pathway, we evaluated alterations in PD-L1 following acquisition of resistance to ALK inhibitors in ALK-positive lung cancer.
Materials and Methods
We established ALK inhibitor-resistant cell lines (H3122CR1, LR1, and CH1) by exposing the parental H3122 ALK-translocated NSCLC cell line to ALK inhibitors. Then, the double-resistant cell lines H3122CR1LR1 and CR1CH1 were developed by exposing the H3122CR1 to other ALK inhibitors. We compared the alterations in PD-L1 expression levels using western blotting, flow cytometry, and quantitative polymerase chain reaction. We also investigated gene expression using RNA sequencing. The expression of PD-L1 in the tumors from 26 ALK-positive metastatic NSCLC patients (11 ALK inhibitor-naïve and 15 ALK inhibitor-resistant patients) was assessed by immunohistochemistry and analyzed.
Results
PD-L1 was expressed at higher levels in ALK inhibitor-resistant cell lines than in the ALK inhibitor-naïve parental cell line at the total protein, surface protein, and mRNA levels. Furthermore, PD-L1 expression in the double-resistant cell lines was much higher than that in the single resistant cell lines. RNA sequencing demonstrated that expression of immune-related genes were largely involved in ALK inhibitor resistance. The mean value of the PD-L1 H-score was 6.5 pre-treatment and 35.0 post-treatment, and the fold difference was 5.42 (p=0.163).
Conclusion
PD-L1 expression increased following acquisition of ALK inhibitor resistance in ALK-positive NSCLC cell lines and tumors.

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Immunomodulatory role of oncogenic alterations in non-small cell lung cancer: a review of implications for immunotherapy
Maritza Ramos-Ramírez, Enrique Caballe-Pérez, José Lucio-Lozada, Eunice Romero-Nuñez, Cesar Castillo-Ruiz, Lorena Dorantes-Sánchez, Diana Flores-Estrada, Gonzalo Recondo, Pedro Barrios-Bernal, Luis Cabrera-Miranda, Heyman Bravo-Dominguez, Norma Hernández-
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Association of PD-L1 expression and clinical outcomes in ROS1 - rearranged advanced non-small cell lung cancer treated with crizotinib
Huixian Zhang, Ziheng Zhang, Ningning Yan, Xingya Li
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Co-Occurrence of ALK rearrangement and KRAS G12C mutation in NSCLC: Report of two cases
M Siringo, F Larocca, A Spagnuolo, G Gentile, M Anile, D Diso, D Santini, A Gelibter
Current Problems in Cancer: Case Reports.2024; 14: 100291. CrossRef
Characterizing the immune tumor microenvironment in ALK fusion-positive lung cancer: state-of-the-art and therapeutical implications
Marco Sposito, Serena Eccher, Luca Pasqualin, Ilaria Mariangela Scaglione, Alice Avancini, Daniela Tregnago, Ilaria Trestini, Jessica Insolda, Adele Bonato, Stefano Ugel, Lisa Derosa, Michele Milella, Sara Pilotto, Lorenzo Belluomini
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Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients
Wenchao Xia, Jing Yang, Hongbin Li, Ling Li, Jinfeng Liu
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High PD-L1 Expression Correlates with an Immunosuppressive Tumour Immune Microenvironment and Worse Prognosis in ALK-Rearranged Non-Small Cell Lung Cancer
Xia Tian, Yalun Li, Qin Huang, Hao Zeng, Qi Wei, Panwen Tian
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Ye Guo, Hanfei Guo, Yongfei Zhang, Jiuwei Cui
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Cancer Research and Treatment.2021; 53(4): 973. CrossRef
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Sara Cavallaro, Petra Hååg, Siddharth S. Sahu, Lorenca Berisha, Vitaliy O. Kaminskyy, Simon Ekman, Rolf Lewensohn, Jan Linnros, Kristina Viktorsson, Apurba Dev
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Haifang Wang, Chen Fu, Jun Du, Hongsheng Wang, Rui He, Xiaofeng Yin, Haixia Li, Xin Li, Hongxia Wang, Kui Li, Lei Zheng, Zongcai Liu, Yurong Qiu
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Lan Wang, Vivian Wai Yan Lui
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Seung Geun Song, Jonghoon Lee, Jaemoon Koh, Sehui Kim, Doo Hyun Chung, Yoon Kyung Jeon
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Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer: Lan Ying Li, Hee Jung Kim, Sun Ae Park, So Hyun Lee, Lee Kyung Kim, Jung Yun Lee, Sunghoon Kim, Young Tae Kim, Sang Wun Kim, Eun Ji Nam; Cancer Res Treat. 2019;51(3):1117-1127. Published online November 6, 2018; DOI: https://doi.org/10.4143/crt.2018.405

Abstract PDF Supplementary Material PubReader ePub

Purpose
Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing.
Materials and Methods
To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA).
Results
Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845).
Conclusion
We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.

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Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib: Seulki Kim, Tae Min Kim, Dong-Wan Kim, Soyeon Kim, Miso Kim, Yong-Oon Ahn, Bhumsuk Keam, Dae Seog Heo; Cancer Res Treat. 2019;51(3):951-962. Published online October 10, 2018; DOI: https://doi.org/10.4143/crt.2018.052

Abstract PDF Supplementary Material PubReader ePub

Purpose
Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1.
Materials and Methods
We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3′ mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines.
Results
We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)‒dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit α (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase α (PI3Kα) inhibitor.
Conclusion
Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.

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Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method: Young Rae Kim, Dongha Kim, Sung Young Kim; Cancer Res Treat. 2019;51(2):672-684. Published online August 10, 2018; DOI: https://doi.org/10.4143/crt.2018.137

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR).
Materials and Methods
Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation.
Results
For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR.
Conclusion
We successfully constructed a multi-study–derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.

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Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells: Ying-ying Xu, Hai-ru Yu, Jia-yi Sun, Zhao Zhao, Shuang Li, Xin-feng Zhang, Zhi-xuan Liao, Ming-ke Cui, Juan Li, Chan Li, Qiang Zhang; Cancer Res Treat. 2019;51(2):576-592. Published online July 18, 2018; DOI: https://doi.org/10.4143/crt.2018.100

Abstract PDF Supplementary Material PubReader ePub

Purpose
Although the interferon α (IFNα) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa.
Materials and Methods
PITX2 expression was assessed in BCa tissues using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels.
Results
PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFNα signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFNα-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozoleelicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFNα-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment.
Conclusion
These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole-resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa.

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Cancer Cell International.2019;[Epub] CrossRef

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Case Report

Rare Mechanism of Acquired Resistance to Osimertinib in Korean Patients with EGFR-mutated Non-small Cell Lung Cancer: Jiyun Lee, Joon Ho Shim, Woong-Yang Park, Hee Kyung Kim, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn; Cancer Res Treat. 2019;51(1):408-412. Published online May 23, 2018; DOI: https://doi.org/10.4143/crt.2018.138

Abstract PDF Supplementary Material PubReader ePub

Epidermal growth factor receptor (EGFR)‒tyrosine kinase inhibitors (TKIs) are effective clinical therapeutics for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib, a thirdgeneration EGFR TKI, has proven effective against T790M mutations. However, the vast majority of patients acquire resistance following successful treatment. A 59-year-old female patient with metastatic NSCLC developed resistance after 43 weeks of osimertinib. CancerSCAN of the metastatic liver lesion revealed a EGFR C797G mutation at an allele frequency of 72%, a preexisting T790M mutation (73%) in cis and an exon 19 deletion (87%). Another 53-year-old female patient developed systemic progression after 10 months of osimertinib. CancerSCAN of the lung biopsy identified an EGFR L718Q mutation at an allele frequency of 7%, concomitant PIK3CA E545K (12.90%) and preexisting EGFR L858R (38%), but loss of the T790M mutation. The heterogeneity of osimertinib resistance mechanisms warrants further investigation into novel or combination agents to overcome the rare acquired resistances.

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Original Articles

Cancer-Associated Fibroblasts Promote the Chemo-resistance in Gastric Cancer through Secreting IL-11 Targeting JAK/STAT3/Bcl2 Pathway: Jun Ma, Xiao Song, Xiaowu Xu, Yiping Mou; Cancer Res Treat. 2019;51(1):194-210. Published online April 20, 2018; DOI: https://doi.org/10.4143/crt.2018.031

Abstract PDF Supplementary Material PubReader ePub

Purpose
Our aim was to detect the potential role of interleukin 11 (IL-11) in the development of chemo-resistance in gastric cancer and to reveal the mechanism involved in the process.
Materials and Methods
Here, we used flow cytometry to examine the percentage of cancer-associated-fibroblasts in tumor samples from chemo-resistant and -sensitive gastric cancer patients. Using MTT assay, we detected the cell viability under different conditions. Using quantitative real-time polymerase chain reaction and Western blotting, we determined the target expressions in mRNA and protein levels. We also performed immunohistochemistry and immunofluorescence to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of IL-11 in chemo-resistant develop in vivo.
Results
Herein, we observed enriched cancer associated fibroblasts in drug resistant tumor tissues from gastric patients. Those fibroblasts facilitate the chemotherapeutic drugs resistance development through the secretion of IL-11, which activates the IL-11/IL-11R/gp130/ JAK/STAT3 anti-apoptosis signaling pathway in gastric cancer cells. We found that the combination of chemotherapeutic drugs and JAK inhibitor overcomes the resistance and increases the survival of mice with gastric cancer xenografts.
Conclusion
Ourresults demonstrated that IL-11 contributed to the obtain ofresistance to chemotherapy drugs through gp130/JAK/STAT3/Bcl2 pathway, and targeting the IL-11 signaling pathway induced by fibroblasts might be a promising strategy to overcome the multi-drugs resistant cancer in clinic.

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CCR6 Is a Predicting Biomarker of Radiosensitivity and Potential Target of Radiosensitization in Rectal Cancer: Hui Chang, Jia-wang Wei, Ya-lan Tao, Pei-rong Ding, Yun-fei Xia, Yuan-hong Gao, Wei-wei Xiao; Cancer Res Treat. 2018;50(4):1203-1213. Published online December 21, 2017; DOI: https://doi.org/10.4143/crt.2017.538

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to explore the functions and mechanisms of C-C motif chemokine receptor 6 (CCR6), a gene associated with progression and metastasis of colorectal cancer (CRC), in radiosensitivity of rectal cancer (RC).
Materials and Methods
RNA sequencing and immunohistochemical analysis on CCR6 expression were performed in pretreatment tissues of RC patients exhibiting different therapeutic effects of radiotherapy. Colonogenic survival assay was conducted in different CRC cell lines to assess their radiosensitivity. And the impact of CCR6 expression on radiosensitivity was validated through RNA interference. The DNA damage repair (DDR) abilities of cell lines with different CCR6 expression were evaluated through immunofluorescence-based γH2AX quantification.
Results
The CCR6 mRNA level was higher in patients without pathologic complete remission (pCR) than in those with pCR (fold changed, 2.11; p=0.004). High-level expression of CCR6 protein was more common in the bad responders than in the good responders (76.3% vs. 37.5%, p < 0.001). The CRC cell lines with higher CCR6 expression (LoVo and sw480) appeared to be more radioresistant, compared with the sw620 cell line which had lower CCR6 expression. CCR6 knockdown made the LoVo cells more sensitive to ionizing radiation (sensitization enhancement ratio, 1.738; p < 0.001), and decreased their DDR efficiency.
Conclusion
CCR6 might affect the RC radiosensitivity through DDR process. These findings supported CCR6 as a predicting biomarker of radiosensitivity and a potential target of radiosensitization for RC patients.

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Participation of CCL1 in Snail-Positive Fibroblasts in Colorectal Cancer Contribute to 5-Fluorouracil/Paclitaxel Chemoresistance: Ziqian Li, Kaying Chan, Yifei Qi, Linlin Lu, Fen Ning, Mengling Wu, Haifang Wang, Yuan Wang, Shaohui Cai, Jun Du; Cancer Res Treat. 2018;50(3):894-907. Published online September 18, 2017; DOI: https://doi.org/10.4143/crt.2017.356

Abstract PDF Supplementary Material PubReader ePub

Purpose
Cancer-associated fibroblasts (CAFs) activated by cancer cells has a central role in development and malignant biological behavior in colorectal cancer (CRC). Adult fibroblasts do not express Snail, but Snail-positive fibroblasts are discovered in the stroma of malignant CRC and reported to be the key role to chemoresistance. However, the reciprocal effect of CAFs expressed Snail to chemoresistance on CRC cells and the underlying molecular mechanisms are not fully characterized.
Materials and Methods
Snail-overexpressed 3T3 stable cell lines were generated by lipidosome and CT26 mixed with 3T3-Snail subcutaneous transplanted CRC models were established by subcutaneous injection. Cell Counting Kit-8, flow cytometry and western blotting assays were performed, and immunohistochemistry staining was studied. The cytokines participated in chemoresistance was validated with reverse transcriptase-polymerase chain reaction and heatmap.
Results
Snail-expression fibroblasts are discovered in human and mouse spontaneous CRCs. Overexpression of Snail induces 3T3 fibroblasts transdifferentiation to CAFs. CT26 co-cultured with 3T3-Snail resisted the impairment from 5-fluorouracil and paclitaxel in vitro. The subcutaneous transplanted tumor models included 3T3-Snail cells develop without restrictions even after treating with 5-fluorouracil or paclitaxel. Moreover, these chemoresistant processes may be mediated by CCL1 secreted by Snail-expression fibroblasts via transforming growth factor β/nuclear factor-κB signaling pathways.
Conclusion
Taken together, Snail-expressing 3T3 fibroblasts display CAFs properties that support 5-fluorouracil and paclitaxel chemoresistance in CRC via participation of CCL1 and suggest that inhibition of the Snail-expression fibroblasts in tumor may be a useful strategy to limit chemoresistance.

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FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation: Jinju Park, Yiseul Choi, Young San Ko, Younghoon Kim, Jung-Soo Pyo, Bo Gun Jang, Min A Kim, Jae-Seon Lee, Mee Soo Chang, Jong-Wan Park, Byung Lan Lee; Cancer Res Treat. 2018;50(1):239-254. Published online March 24, 2017; DOI: https://doi.org/10.4143/crt.2016.580

Abstract PDF PubReader ePub

Purpose
Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells.
Materials and Methods
Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed.
Results
SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin.
Conclusion
FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

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Upregulation of MicroRNA-1246 Is Associated with BRAF Inhibitor Resistance in Melanoma Cells with Mutant BRAF: Jae-Hyeon Kim, Jun-Ho Ahn, Michael Lee; Cancer Res Treat. 2017;49(4):947-959. Published online January 3, 2017; DOI: https://doi.org/10.4143/crt.2016.280

Abstract PDF Supplementary Material PubReader ePub

Purpose
Intrinsic and acquired resistance limit the therapeutic benefits of inhibitors of oncogenic BRAF in melanoma. To identify microRNAs (miRNAs) associated with resistance to a BRAF inhibitor, we compared miRNA expression levels in three cell lines with different BRAF inhibitor sensitivity.
Materials and Methods
miRNA microarray analysis was conducted to compare miRNA expression levels. Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to confirm the expression of differentially expressed miRNAs. The cellular effects of miR-1246 were further examined by MTT assay, immunoblotting analysis, cell cycle analysis, flow cytometric assay of apoptosis, and autophagy assay.
Results
The miRNA microarray analysis and qRT-PCR identified five miRNAs (miR-3617, miR-92a-1, miR-1246, miR-193b-3p, and miR-17-3p) with expression that was consistently altered in two BRAF inhibitor-resistant cell lines. Among the five miRNAs, a miR-1246 mimic significantly reduced the antiproliferative effects of the BRAF inhibitor PLX4720 in BRAF inhibitor–resistant A375P (A375P/Mdr) cells, suggesting that miR-1246 upregulation confers acquired resistance to BRAF inhibition. In particular, apoptosis was identified as a major type of cell death in miR-1246–transfected cells; however, necrosis predominated in mimic-control-transfected cells, indicating that the resistance to PLX4720 in miR-1246 mimic-transfected cells is predominantly due to a reduction in necrosis. Furthermore, we found that miR-1246 promoted G2/M arrest through autophagy as a way to escape cell death by necrosis and apoptosis in response to PLX4720. The promotion of BRAF inhibitor resistance by miR-1246 was associated with lowered levels of p-ERK.
Conclusion
These results suggest that miR-1246 may be a potential therapeutic target in melanoma with acquired resistance to BRAF inhibitors.

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Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma: Young-Bem Se, Seung Hyun Kim, Ji Young Kim, Ja Eun Kim, Yun-Sik Dho, Jin Wook Kim, Yong Hwy Kim, Hyun Goo Woo, Se-Hyuk Kim, Shin-Hyuk Kang, Hak Jae Kim, Tae Min Kim, Soon-Tae Lee, Seung Hong Choi, Sung-Hye Park, Il Han Kim, Dong Gyu Kim, Chul-Kee Park; Cancer Res Treat. 2017;49(2):387-398. Published online July 19, 2016; DOI: https://doi.org/10.4143/crt.2016.106

Abstract PDF Supplementary Material PubReader ePub

Purpose
Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance.
Materials and Methods
The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis.
Results
The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith lowHOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified.
Conclusion
The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

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Intratumoral IL-12 delivery via mesenchymal stem cells combined with PD-1 blockade leads to long-term antitumor immunity in a mouse glioblastoma model
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Biomedicine & Pharmacotherapy.2024; 173: 115790. CrossRef
Dihydropyrimidinase‐like 2 can serve as a novel therapeutic target and prognostic biomarker in acute myeloid leukemia
Fenglin Li, Qing Ling, Jiaying Lian, Ying Chen, Chao Hu, Min Yang, Xiang Zhang, Chenying Li, Shihui Mao, Wenle Ye, Xia Li, Xiangjie Lin, Wenwen Wei, Xin Huang, Jiajia Pan, Yu Qian, Jinghan Wang, Ying Lu, Jie Jin
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Development and validation of a predictive model in diagnosis and prognosis of primary glioblastoma patients based on Homeobox A family
Zong-Qing Zheng, Gui-Qiang Yuan, Guo-Guo Zhang, Qian-Qian Nie, Zhong Wang
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HOXA11-AS aggravates microglia-induced neuroinflammation after traumatic brain injury
Xiang-Long Li, Bin Wang, Fu-Bing Yang, Li-Gang Chen, Jian You
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Molecular implications of HOX genes targeting multiple signaling pathways in cancer
U Sangeetha Shenoy, Divya Adiga, Shama Prasada Kabekkodu, Keith D Hunter, Raghu Radhakrishnan
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HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours
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Expression Profile and Prognostic Values of HOXA Family Members in Laryngeal Squamous Cell Cancer
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Methylation in HOX Clusters and Its Applications in Cancer Therapy
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Zewei Tu, Lei Wu, Peng Wang, Qing Hu, Chuming Tao, Kuangxun Li, Kai Huang, Xingen Zhu
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Ricardo Bonfim-Silva, Fernanda Ursoli Ferreira Melo, Carolina Hassibe Thomé, Kuruvilla Joseph Abraham, Fábio Augusto Labre De Souza, Fernando Silva Ramalho, Hélio Rubens Machado, Ricardo Santos De Oliveira, Angelo A. Cardoso, Dimas Tadeu Covas, Aparecida
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Long non-coding RNA HOXA11-AS promotes cell proliferation and metastasis in human breast cancer
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Identification of skin-related lncRNAs as potential biomarkers that are involved in Wnt pathways in keloids
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Expression of Myxovirus Resistance A (MxA) Is Associated with Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Breast Cancers: So Jeong Lee, Cheong-Soo Hwang, Young-Keum Kim, Hyun Jung Lee, Sang-Jeong Ahn, Nari Shin, Jung Hee Lee, Dong Hoon Shin, Kyung Un Choi, Do Youn Park, Chang Hun Lee, Gi Young Huh, Mi Young Sol, Hee Jin Lee, Gyungyub Gong, Jee Yeon Kim, Ahrong Kim; Cancer Res Treat. 2017;49(2):313-321. Published online July 7, 2016; DOI: https://doi.org/10.4143/crt.2016.098

Abstract PDF PubReader ePub

Purpose
The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been determined in breast cancers. Interferons can affect T-cell activity through direct and indirect mechanisms. Myxovirus resistance A (MxA) is an excellent marker of interferon activity. Here,we evaluated TILs and MxA expression in human epidermal growth factor receptor 2 (HER2)–positive breast cancers.
Materials and Methods
Ninety cases of hormone receptor (HR)+/HER2+ tumors and 78 cases of HR–/HER2+ tumors were included. The TILs level was assessed using hematoxylin and eosin–stained full face sections, and MxA expressionwas evaluated by immunohistochemistrywith a tissue microarray.
Results
MxA protein expression was significantly higher in tumors with high histologic grade (p=0.023) and high levels of TILs (p=0.002). High levels of TILs were correlated with high histological grade (p=0.001), negative lymphovascular invasion (p=0.007), negative lymph node metastasis (p=0.007), absence of HR expression (p < 0.001), abundant tertiary lymphoid structures (TLSs) around ductal carcinoma in situ (p=0.018), and abundant TLSs around the invasive component (p < 0.001). High levels of TILs were also associated with improved disease-free survival, particularly in HR–/HER2+ breast cancers. However, MxA was not a prognostic factor.
Conclusion
High expression of MxA in tumor cells was associated with high levels of TILs in HER2-positive breast cancers. Additionally, a high level of TILs was a prognostic factor for breast cancer, whereas the level of MxA expression had no prognostic value.

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Yuki Sato, Karina Silina, Maries van den Broek, Kiyoshi Hirahara, Motoko Yanagita
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Scientific Reports.2017;[Epub] CrossRef

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Review Article

Treatment of Non-small Cell Lung Carcinoma after Failure of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: Jae Cheol Lee, Seung Hun Jang, Kye Young Lee, Young-Chul Kim; Cancer Res Treat. 2013;45(2):79-85. Published online June 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.2.79

Abstract PDF PubReader ePub

Since the first description of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, studies have proved EGFR tyrosine kinase inhibitors (TKIs) as a first choice of treatment. The median response duration of TKIs as a first-line treatment for EGFR mutant tumors ranges from 11 to 14 months. However, acquired resistance to EGFR-TKIs is inevitable due to various mechanisms, such as T790M, c-Met amplification, activation of alternative pathways (IGF-1, HGF, PI3CA, AXL), transformation to mesenchymal cell or small cell features, and tumor heterogeneity. Until development of a successful treatment strategy to overcome such acquired resistance, few options are currently available. Here we provide a summary of the therapeutic options after failure of first line EGFR-TKI treatment for NSCLC.

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Andrés F. Cardona, Oscar Arrieta, Martín Ignacio Zapata, Leonardo Rojas, Beatriz Wills, Noemí Reguart, Niki Karachaliou, Hernán Carranza, Carlos Vargas, Jorge Otero, Pilar Archila, Claudio Martín, Luis Corrales, Mauricio Cuello, Carlos Ortiz, Luis E. Pino
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Noemi Picco, Erik Sahai, Philip K. Maini, Alexander R.A. Anderson
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Woo‐Jin Kim, Sunmin Kim, Hayoung Choi, Jinsun Chang, Hong‐Joon Shin, Cheol‐Kyu Park, In‐Jae Oh, Kyu‐Sik Kim, Young‐Chul Kim, Yoo‐Duk Choi
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Peptide Nucleic Acid Clamping Versus Direct Sequencing for the Detection of EGFR Gene Mutation in Patients with Non-small Cell Lung Cancer
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Original Article

Constitutive Expression of MAP Kinase Phosphatase-1 Confers Multi-drug Resistance in Human Glioblastoma Cells: Hana Yu, Junseong Park, Jungsul Lee, Kyungsun Choi, Chulhee Choi; Cancer Res Treat. 2012;44(3):195-201. Published online September 30, 2012; DOI: https://doi.org/10.4143/crt.2012.44.3.195

Abstract PDF PubReader ePub

PURPOSE
Current treatment of glioblastoma after surgery consists of a combination of fractionated radiotherapy and temozolomide. However, it is difficult to completely remove glioblastoma because it has uncertain boundaries with surrounding tissues. Moreover, combination therapy is not always successful because glioblastoma has diverse resistances. To overcome these limitations, we examined the combined effects of chemotherapy and knockdown of mitogen-activated protein kinase phosphatase-1 (MKP-1).
MATERIALS AND METHODS
We used ten different anti-cancer drugs (cisplatin, cyclophosphoamide, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, mitomycin C, and vincristine) to treat glioblastoma multiforme (GBM) cells. Knockdown of MKP-1 was performed using siRNA and lipofectamine. The basal level of MKP-1 in GBM was analyzed based on cDNA microarray data obtained from the Gene Expression Omnibus (GEO) databases.
RESULTS
Anti-cancer drug-induced cell death was significantly enhanced by knockdown of MKP-1, and this effect was most prominent in cells treated with irinotecan and etoposide. Treatment with these two drugs led to significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in a time-dependent manner, while pharmacological inhibition of JNK partially inhibited drug-induced cell death. Knockdown of MKP-1 also enhanced drug-induced phosphorylation of JNK.
CONCLUSION
Increased MKP-1 expression levels could be the cause of the high resistance to conventional chemotherapeutics in human GBM. Therefore, MKP-1 is an attractive target for overcoming drug resistance in this highly refractory malignancy.

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Review Articles

Epithelial Mesenchymal Transition in Drug Resistance and Metastasis of Lung Cancer: Fariz Nurwidya, Fumiyuki Takahashi, Akiko Murakami, Kazuhisa Takahashi; Cancer Res Treat. 2012;44(3):151-156. Published online September 30, 2012; DOI: https://doi.org/10.4143/crt.2012.44.3.151

Abstract PDF PubReader ePub

Among all types of cancer, incidence of lung cancer remains the highest with regard to cancer-related mortality. Problems contributing to recurrence of the disease include metastasis and drug resistance. Mounting evidence has demonstrated involvement of epithelial mesenchymal transition (EMT) in cancer progression. EMT is a critical mechanism ensuring tissue remodeling during morphogenesis of multicellular organisms. Therefore, understanding of the biology of this process for identification of potential EMT-targeted therapeutic strategies for the benefit cancer patients is necessary. This review describes recent evidence of EMT involvement in drug resistance and metastasis of cancers, with an emphasis on lung cancer.

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Present Status and Problems on Molecular Targeted Therapy of Cancer: Nagahiro Saijo; Cancer Res Treat. 2012;44(1):1-10. Published online March 31, 2012; DOI: https://doi.org/10.4143/crt.2012.44.1.1

Abstract PDF PubReader ePub

Numerous clinical trials of molecular targeted drugs for cancer have been conducted, with remarkable results for certain drugs and accumulation of "negative data" causing a hitch in the development plan for some other compounds. Five recent issues and problems of molecular targeted therapies were discussed critically. Drug discovery and effects against driver mutations (activating mutations) and problems: possibility for circumventing inherent and acquired resistance with the aim of achieving radical cure. Synthetic lethality: reasonable patient selection in individualized treatment strategy. Response rate and progression-free survival improvement with or without overall survival benefit and enhancement of toxicity in bevacizumab therapy: best endpoints for the evaluation of effect of antiangiogenic therapy. Negative data on small-molecule targeted therapy, primarily vascular endothelial growth factor tyrosine kinase inhibitors: loose GO or NO-GO decision criteria for further development of new compounds in early clinical trials. Effect of immunotherapy: difficulty to verify by proof of principle study. We are faced to many questions for the development of efficient personalized therapy. Accumulation of scientific global preclinical and clinical evidences is essential to use these new therapeutic modalities for the improvement of oncologic health care.

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Original Article

Characterization of RhoA-mediated Chemoresistance in Gastric Cancer Cells: Won Ki Kang, Inkyoung Lee, Chaehwa Park; Cancer Res Treat. 2005;37(4):251-256. Published online August 31, 2005; DOI: https://doi.org/10.4143/crt.2005.37.4.251

Abstract PDF PubReader ePub

Purpose

RhoA is a critical transducer of extracellular signals, which leads to organization of actin cytoskeleton, motility, adhesion and gene regulation. The present study aimed to explore whether RhoA influences the susceptibility of gastric cancer cells to chemotherapeutic drugs.

Materials and Methods

SNU638 cells were transfected with a mock vector (pcDNA3.1), RhoA (pcDNA/RhoA), or constitutively active RhoA (pcDNA/caRhoA). MTT assay and Western blot analysis were performed to study the growth response to several chemotherapeutic drugs in the gastric cancer cell line, SNU638, with different RhoA levels.

Results

RhoA significantly enhanced the resistance to lovastatin, 5-FU, taxol and vincristine, but did not affect the sensitivity to cisplatin or etoposide in SNU638. In the Western blot analysis, RhoA decreased the PARP cleavage, which was accompanied by a concurrent reductionin cell death. The gene expression profile after a cDNA microarray analysis demonstrated that RhoA was associated with the differential expression of 19 genes, including those involved in anti-oxidant defense, glucose metabolism, anti-apoptosis and protein turnover.

Conclusion

Gastric cancer cells with a high expression of RhoA could be resistant to chemotherapeutic drugs, such as taxol or vincristine, implying that treatment strategies aimed at inactivation of RhoA might be promising for improving the efficacy of these chemotherapeutic drugs.

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