Cancer Research and Treatment

Original Articles

Lung and Thoracic cancer

Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer: Shinkyo Yoon, Hannah Yang, Hyun-Min Ryu, Eunjin Lee, Yujin Jo, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Wanlim Kim, Kyung Hae Jung, Sook Ryun Park, Eun Kyung Choi, Sang-We Kim, Kang-Seo Park, Dae Ho Lee; Cancer Res Treat. 2022;54(3):767-781. Published online September 30, 2021; DOI: https://doi.org/10.4143/crt.2021.651

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Purpose
Heat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.
Materials and Methods
We established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.
Results
We identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.
Conclusion
The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

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Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis
Dihua Huang, Feng Xu, Luohang Xu, Zekai Tang, Yanxin Hu, Jiandong Li, Jianhua Yu
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2025; 1871(5): 167814. CrossRef
Integrins in Cancer Drug Resistance: Molecular Mechanisms and Clinical Implications
Yoshinobu Kariya, Michiru Nishita
International Journal of Molecular Sciences.2025; 26(7): 3143. CrossRef
Integrin αV Inhibition by GMI, a Ganoderma Microsporum Immunomodulatory Protein, Abolish Stemness and Migration in EGFR‐Mutated Lung Cancer Cells Resistant to Osimertinib
Yu‐Ting Kang, Hui‐Yi Chang, Ya‐Chu Hsieh, Chia‐Hsuan Chou, I‐Lun Hsin, Jiunn‐Liang Ko
Environmental Toxicology.2024; 39(12): 5238. CrossRef
Junctional adhesion molecular 3 (JAM3) is a novel tumor suppressor and improves the prognosis in breast cancer brain metastases via the TGF-β/Smad signal pathway
Kaitao Zhu, Shiwei Li, Hongru Yao, Jilong Hei, WenGuo Jiang, Tracey Martin, Shanyi Zhang
Journal of Neuro-Oncology.2024; 170(2): 331. CrossRef
Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence
Bashar Alhasan, Marina Mikeladze, Irina Guzhova, Boris Margulis
Cancer and Metastasis Reviews.2023; 42(1): 217. CrossRef

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Can Serum be Used for Analyzing the KRAS Mutation Status in Patients with Advanced Colorectal Cancer?: Seung Tae Kim, Won Jin Chang, Lihua Jin, Jae Sook Sung, Yun Ji Choi, Yeul Hong Kim; Cancer Res Treat. 2015;47(4):796-803. Published online January 30, 2015; DOI: https://doi.org/10.4143/crt.2014.106

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Purpose
KRAS mutations have been used widely as prognostic or predictive marker in patients with advanced colorectal cancer (CRC). However, it may be difficult to obtain a tumor tissue for analyzing the status of KRAS mutation in large proportion of patients with advanced disease.
Materials and Methods
We obtained pairs of tumor and serum samples from 65 patients with advanced CRC, between March 2008 and July 2011. KRAS mutation status from the tumor samples was analyzed by genomic polymerase chain reaction and direct sequence, and KRASmutation status from the serum samples was determined by a genomic polymerase chain reaction– restriction fragment length polymorphism assay.
Results
KRAS mutations were detected in the serum samples of 26 patients and in the tumor samples of 31 patients. KRAS mutation status in the serum and tumor samples was consistent in 44 of the 65 pairs (67.7%). There was a significant correlation between the mutations detected in the serum sample and the mutations detected in the matched tumor sample (correlation index, 0.35; p < 0.004). Twenty-two of the 57 patients (38.5%) received anti-epidermal growth factor receptor therapy as any line therapy. There was no significant difference in the overall survival (OS) in accordance to the status of KRASmutations in both the serum and tumor samples (p > 0.05). In a multivariate analysis, liver metastasis and no cytoreductive operation were independent prognostic factors for decreased OS.
Conclusion
The serum sample might alternatively be used when it is difficult to obtain tumor tissues for analyzing the status of KRAS mutation in patients with advanced CRC.

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The Prognostic Utility of KRAS Mutations in Tissue and Circulating Tumour DNA in Colorectal Cancer Patients
Joel Petit, Georgia Carroll, Jie Zhao, Peter Pockney, Rodney J. Scott
Gastroenterology Insights.2024; 15(1): 107. CrossRef
Effect of CIP2A and its mechanism of action in the malignant biological behavior of colorectal cancer
Wei Chen, Jing-Lin Liang, Kai Zhou, Qing-Li Zeng, Jun-Wen Ye, Mei-Jin Huang
Cell Communication and Signaling.2020;[Epub] CrossRef
The diagnostic accuracy of circulating free DNA for the detection of KRAS mutation status in colorectal cancer: A meta‐analysis
Wenli Xie, Li Xie, Xianrang Song
Cancer Medicine.2019; 8(3): 1218. CrossRef
Prognostic value of circulating cell-free DNA in patients with pancreatic cancer: A systemic review and meta-analysis
Linyan Chen, Yi Zhang, Yuan Cheng, Dan Zhang, Sha Zhu, Xuelei Ma
Gene.2018; 679: 328. CrossRef
The prognostic value of KRAS mutation by cell-free DNA in cancer patients: A systematic review and meta-analysis
Rongyuan Zhuang, Song Li, Qian Li, Xi Guo, Feng Shen, Hong Sun, Tianshu Liu, Alvaro Galli
PLOS ONE.2017; 12(8): e0182562. CrossRef

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Dose KRAS Mutation Status Affect on the Effect of VEGF Therapy in Metastatic Colon Cancer Patients?: Seung Tae Kim, Kyong Hwa Park, Sang Won Shin, Yeul Hong Kim; Cancer Res Treat. 2014;46(1):48-54. Published online January 15, 2014; DOI: https://doi.org/10.4143/crt.2014.46.1.48

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PURPOSE
Mutations affecting the KRAS gene are an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, the role of KRAS mutation as a biomarker for anti-vascular endothelial growth factor (VEGF) remains controversial.
MATERIALS AND METHODS
We analyzed retrospective data from 32 CRC patients who were available for KRAS mutation status and received cytotoxic chemotherapy plus bevacizumab as a first-line therapy. Six of 32 patients received anti-EGFR therapies. We used KRAS mutation status as a predictive or prognostic factor in CRC patients receiving bevacizumab.
RESULTS
We observed mutations in KRAS in 59.4% of patients. Bevacizumab was used in combination with oxaliplatin based regimens. There was no significant difference for progression free survival (PFS) and overall survival (OS) in patients with oxaliplatin based cytotoxic chemotherapy plus bevacizumab according to the status of KRAS mutation. After first-line therapy, 28 patients (87.5%) received second-line therapy. In univariate analysis, KRAS mutations did not have a major prognostic value for PFS (hazard ratio, 1.007; 95% confidence interval [CI], 0.469 to 2.162; p>0.05) or OS (hazard ratio, 0.548; 95% CI, 0.226 to 1.328; p>0.05). In addition, anti-EGFR therapies did not affect the impact on OS.
CONCLUSION
KRAS mutation is neither a predictive for bevacizumab nor a prognostic for OS in CRC patients receiving anti-VEGF therapy.

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The KRAS-Mutant Consensus Molecular Subtype 3 Reveals an Immunosuppressive Tumor Microenvironment in Colorectal Cancer
Pariyada Tanjak, Amphun Chaiboonchoe, Tharathorn Suwatthanarak, Onchira Acharayothin, Kullanist Thanormjit, Jantappapa Chanthercrob, Thanawat Suwatthanarak, Bundit Wannasuphaphol, Kemmapon Chumchuen, Bhoom Suktitipat, Somponnat Sampattavanich, Krittiya Ko
Cancers.2023; 15(4): 1098. CrossRef
Evaluation of the Prognostic Value of Low-Frequency KRAS Mutation Detection in Circulating Tumor DNA of Patients with Metastatic Colorectal Cancer
Chien-Yu Lin, Ming-Yin Shen, William Tzu-Liang Chen, Chin-An Yang
Journal of Personalized Medicine.2023; 13(7): 1051. CrossRef
Advances in Tumor-Stroma Interactions: Emerging Role of Cytokine Network in Colorectal and Pancreatic Cancer
Chiara Bazzichetto, Fabiana Conciatori, Italia Falcone, Francesco Cognetti, Michele Milella, Ludovica Ciuffreda
Journal of Oncology.2019; 2019: 1. CrossRef
Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis
Javier Garde Noguera, Eloisa Jantus-Lewintre, Mireia Gil-Raga, Elena Evgenyeva, Sonia Maciá Escalante, Antonio Llombart-Cussac, Carlos Camps Herrero
Molecular and Clinical Oncology.2017; 6(3): 403. CrossRef
MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation
Yuan Wang, Ping Yan, Zhentao Liu, Xiaodan Yang, Yaping Wang, Zhirong Shen, Hua Bai, Jie Wang, Zhijie Wang
Thoracic Cancer.2016; 7(3): 279. CrossRef
Medullary carcinoma of the colon: can the undifferentiated be differentiated?
Anne-Marie Kanstrup Fiehn, Morten Grauslund, Anders Glenthøj, Linea Cecilie Melchior, Ben Vainer, Gro Linno Willemoe
Virchows Archiv.2015; 466(1): 13. CrossRef
Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts
Hiroshi Tsukihara, Fumio Nakagawa, Kazuki Sakamoto, Keiji Ishida, Nozomu Tanaka, Hiroyuki Okabe, Junji Uchida, Kenichi Matsuo, Teiji Takechi
Oncology Reports.2015;[Epub] CrossRef
CSBF/C10orf99, a novel potential cytokine, inhibits colon cancer cell growth through inducing G1 arrest
Wen Pan, Yingying Cheng, Heyu Zhang, Baocai Liu, Xiaoning Mo, Ting Li, Lin Li, Xiaojing Cheng, Lianhai Zhang, Jiafu Ji, Pingzhang Wang, Wenling Han
Scientific Reports.2014;[Epub] CrossRef

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Impact of KRAS Mutation Status on Outcomes in Metastatic Colon Cancer Patients without Anti-Epidermal Growth Factor Receptor Therapy: Seung Tae Kim, Kyong Hwa Park, Jun Suk Kim, Sang Won Shin, Yeul Hong Kim; Cancer Res Treat. 2013;45(1):55-62. Published online March 31, 2013; DOI: https://doi.org/10.4143/crt.2013.45.1.55

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PURPOSE
Activating mutation of the KRAS oncogene is an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, KRAS mutation as a prognostic factor of survival outcome remains controversial in CRC, independent of anti-EGFR therapies.
MATERIALS AND METHODS
We conducted a retrospective analysis of 103 CRC patients who were available for evaluation of KRAS mutation status. None of the patients analyzed had received anti-EGFR therapies. The role of KRAS mutation status was evaluated as a predictive factor for oxaliplatin or irinotecan and as a prognostic factor in CRC patients who did not receive anti-EGFR therapies.
RESULTS
Mutations in KRAS were observed in 48.5% of patients. The response for oxaliplatin- (p=0.664) and irinotecan-based (p=0.255) cytotoxic chemotherapy did not differ according to the KRAS mutation status. In addition, no significant difference in progression free survival (PFS; oxaliplatin, p=0.583 and irinotecan, p=0.426) and overall survival (OS; p=0.258) was observed between the wild and mutant type of the KRAS gene. In univariate and multivariate analyses, KRAS mutations did not have a major prognostic value regarding PFS (oxaliplatin: hazard ratio, 0.892; 95% confidence interval [CI], 0.590 to 1.347; p=0.586 and irinotecan: hazard ratio, 0.831; 95% CI, 0.524 to 1.319; p=0.433) or OS (hazard ratio, 0.754; 95% CI, 0.460 to 1.236; p=0.263). In addition, anti-vascular endothelial growth factor therapies did not affect PFS to oxaliplatin or irinotecan and OS.
CONCLUSION
KRAS mutation is not a prognostic marker for PFS to oxaliplatin or irinotecan and OS in CRC patients who did not receive anti-EGFR therapies.

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The Landscape of PIK3CA Mutations in Colorectal Cancer
Ioannis A. Voutsadakis
Clinical Colorectal Cancer.2021; 20(3): 201. CrossRef
Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives
Gianluca Pellino, Gaetano Gallo, Pierlorenzo Pallante, Raffaella Capasso, Alfonso De Stefano, Isacco Maretto, Umberto Malapelle, Shengyang Qiu, Stella Nikolaou, Andrea Barina, Giuseppe Clerico, Alfonso Reginelli, Antonio Giuliani, Guido Sciaudone, Christo
Gastroenterology Research and Practice.2018; 2018: 1. CrossRef
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Michael J. Magnetta, Anish Ghodadra, Steven J. Lahti, Minzhi Xing, Di Zhang, Hyun S. Kim
Abdominal Radiology.2017; 42(2): 451. CrossRef
C1QBP is upregulated in colon cancer and binds to apolipoprotein A-I
Kun Kim, Min-Jeong Kim, Kyung-Hee Kim, Sun-A Ahn, Jong Heon Kim, Jae Youl Cho, Seung-Gu Yeo
Experimental and Therapeutic Medicine.2017; 13(5): 2493. CrossRef
Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis
Javier Garde Noguera, Eloisa Jantus-Lewintre, Mireia Gil-Raga, Elena Evgenyeva, Sonia Maciá Escalante, Antonio Llombart-Cussac, Carlos Camps Herrero
Molecular and Clinical Oncology.2017; 6(3): 403. CrossRef
Up-front systemic chemotherapy is a feasible option compared to primary tumor resection followed by chemotherapy for colorectal cancer with unresectable synchronous metastases
Hiroaki Niitsu, Takao Hinoi, Manabu Shimomura, Hiroyuki Egi, Minoru Hattori, Yasuyo Ishizaki, Tomohiro Adachi, Yasufumi Saito, Masashi Miguchi, Hiroyuki Sawada, Masatoshi Kochi, Shoichiro Mukai, Hideki Ohdan
World Journal of Surgical Oncology.2015;[Epub] CrossRef
KRAS Status as an Independent Prognostic Factor for Survival after Yttrium-90 Radioembolization Therapy for Unresectable Colorectal Cancer Liver Metastases
Steven J. Lahti, Minzhi Xing, Di Zhang, James J. Lee, Michael J. Magnetta, Hyun S. Kim
Journal of Vascular and Interventional Radiology.2015; 26(8): 1102. CrossRef
Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer
LEE CHENG PHUA, HUI WEN NG, ANGIE HUI LING YEO, ELYA CHEN, MICHELLE SHU MEI LO, PEH YEAN CHEAH, ERIC CHUN YONG CHAN, POH KOON KOH, HAN KIAT HO
Oncology Letters.2015; 10(4): 2519. CrossRef
Characterization of rare transformingKRASmutations in sporadic colorectal cancer
Joanna HM Tong, Raymond WM Lung, Frankie MC Sin, Peggy PY Law, Wei Kang, Anthony WH Chan, Brigette BY Ma, Tony WC Mak, Simon SM Ng, Ka Fai To
Cancer Biology & Therapy.2014; 15(6): 768. CrossRef
Beyond KRAS: Predictive factors of the efficacy of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer
Alfonso De Stefano
World Journal of Gastroenterology.2014; 20(29): 9732. CrossRef
RAS mutations: impact on treatment outcome
Sameh Mikhail, Tanios Bekaii-Saab
Colorectal Cancer.2013; 2(6): 525. CrossRef
The prognostic values of EGFR expression and KRAS mutation in patients with synchronous or metachronous metastatic colorectal cancer
Ching-Wen Huang, Hsiang-Lin Tsai, Yi-Ting Chen, Chun-Ming Huang, Cheng-Jen Ma, Chien-Yu Lu, Chao-Hung Kuo, Deng-Chyang Wu, Chee-Yin Chai, Jaw-Yuan Wang
BMC Cancer.2013;[Epub] CrossRef

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