Cancer Research and Treatment

Original Articles

Lung Cancer

The Clinical Impact of Capmatinib in the Treatment of Advanced Non–Small Cell Lung Cancer with MET Exon 14 Skipping Mutation or Gene Amplification: Wonyoung Choi, Seog-Yun Park, Youngjoo Lee, Kun Young Lim, Minjoung Park, Geon Kook Lee, Ji-Youn Han; Cancer Res Treat. 2021;53(4):1024-1032. Published online January 29, 2021; DOI: https://doi.org/10.4143/crt.2020.1331

Abstract PDF Supplementary Material PubReader ePub

Purpose
Capmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non–small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification.
Materials and Methods
Patients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients’ clinical outcome were retrospectively reviewed.
Results
A total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123).
Conclusion
Our data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

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Exploring Cellular Plasticity and Resistance Mechanisms in Lung Cancer: Innovations and Emerging Therapies
Caiyu Jiang, Shenglong Xie, Kegang Jia, Gang Feng, Xudong Ren, Youyu Wang
Journal of Pharmaceutical Analysis.2025; : 101179. CrossRef
EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma
Ann-Katrin Piper, Chelsea Penney, Jacqueline Holliday, Gary Tincknell, Yafeng Ma, Sarbar Napaki, Klaus Pantel, Daniel Brungs, Marie Ranson
International Journal of Molecular Sciences.2024; 25(10): 5565. CrossRef
Understanding the treatment response and resistance to targeted therapies in non-small cell lung cancer: clinical insights and perspectives
Hang Zhang, Yingying Zhang, Yingying Zhu, Tian Dong, Zheng Liu
Frontiers in Oncology.2024;[Epub] CrossRef
Synthesis and bioassay of 3-Aryl -1-(pyridin-4-yl)benzo[4,5]imidazo[1,2-d][1,2,4]- triazin-4(3H)-ones as anti-cancer agents
Bassam Abu Thaher, Ihab Al-Masri, Kanan Wahedy, Rami Morjan, Saeb Aliwaini, Iman Mahmoud Al atter, Aayat Ahmed Elmabhouh, Areej khaled AL ibwaini, Saba Luay Alkhaldi, Basem Qeshta, Claus Jacob, Hans-Peter Deigner
Naunyn-Schmiedeberg's Archives of Pharmacology.2023; 396(8): 1797. CrossRef
RNA splicing alterations in lung cancer pathogenesis and therapy
Yueren Yan, Yunpeng Ren, Yufang Bao, Yongbo Wang
Cancer Pathogenesis and Therapy.2023; 1(4): 272. CrossRef
Clinicopathological characteristics of Non-Small Cell Lung Cancer (NSCLC) patients with c-MET exon 14 skipping mutation, MET overexpression and amplification
Caixia Ding, Yanyi Qiu, Juan Zhang, Wei Wei, Hongbian Gao, Yong Yuan, Xiaomin Wang
BMC Pulmonary Medicine.2023;[Epub] CrossRef
Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations
Shun Lu, Jian Fang, Xingya Li, Lejie Cao, Jianying Zhou, Qisen Guo, Zongan Liang, Ying Cheng, Liyan Jiang, Nong Yang, Zhigang Han, Jianhua Shi, Yuan Chen, Hua Xu, Helong Zhang, Gongyan Chen, Rui Ma, Sanyuan Sun, Yun Fan, Songhua Fan, Jie Yu, Puhan Lu, Xia
JTO Clinical and Research Reports.2022; 3(10): 100407. CrossRef
HPLC with Fluorescence and Photodiode Array Detection for Quantifying Capmatinib in Biological Samples: Application to In Vivo and In Vitro Studies
Aref Zayed, Sana’a A. Jaber, Jomana Al Hroot, Sahar Hawamdeh, Nehad M. Ayoub, Nidal A. Qinna
Molecules.2022; 27(23): 8582. CrossRef
Evaluation of MET alteration in EGFR-mutant non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitor from paired biopsy: A retrospective cohort study
Bo Mi Ku, Sungwon Park, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Yoon-La Choi, Myung-Ju Ahn
Precision and Future Medicine.2022; 6(4): 233. CrossRef
Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics
Matthew Z Guo, Kristen A Marrone, Alexander Spira, David M Waterhouse, Susan C Scott
OncoTargets and Therapy.2021; Volume 14: 5321. CrossRef

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Co-Expression of Cox-2, C-Met and β-catenin in Cells Forming Invasive front of Gallbladder Cancer: Woo Sung Moon, Ho Sung Park, Ho Lee, Rama Pai, Andrzej S. Tarnawski, Kyung Ryoul Kim, Kyu Yun Jang; Cancer Res Treat. 2005;37(3):171-176. Published online June 30, 2005; DOI: https://doi.org/10.4143/crt.2005.37.3.171

Abstract PDF PubReader ePub

Purpose

Gallbladder cancer is a malignancy with poor prognosis, predominantly resulting from invasion and metastasis. Our previous studies have demonstrated that prostaglandin E₂ (PGE₂), generated by cyclooxygenase 2 (Cox-2), transactivates epidermal growth factor receptor (EGFR), c-Met and β-catenin; thus, enhancing colon cancer cell growth and invasiveness in vitro. To determine whether these findings are applicable to clinical conditions, we examined the expression and cellular localization/co-localization of Cox-2, c-Met, β-catenin, EGFR and c-erbB2 in gallbladder cancer.

Materials and Methods

Thirty-five specimens of invasive gallbladder cancer, 8 in situ carcinoma and 7 adenoma specimens were immunostained with specific antibodies against Cox-2, c-Met, β-catenin, EGFR and c-erbB2. The cellular distribution, localization and colocalization were examined, and the signal intensities quantified in: a) the central area of gallbladder cancer and b) cancer cells forming the invasive front.

Results

Cox-2, c-Met, β-catenin, c-erbB2 and EGFR were over-expressed in 80, 74, 71, 62 and 11% of invasive gallbladder cancers, respectively. β-catenin was expressed in 80% of non-malignant specimens, exclusively in the cell membrane, while the cancer specimens showed cytoplasmic and/or nuclear staining. Significantly higher Cox-2, c-Met and β-catenin expressions were present in cancer cells of the invasive front than in the tumor central areas (p<0.001), and these expressions were significantly (p=0.01) associated with the invasion depth. Co-expressions of Cox-2, c-Met, β-catenin and c-erbB2 were present in 42% of the specimens in cancer cells forming the invasive front.

Conclusion

The overexpressions, and often co-localizations, of Cox-2, c-Met and β-catenin in cancer cells forming the invasive front indicate their local interactions and important roles in invasion.

Citations

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EGFR, HER2, and MET gene amplification and protein expression profiles in biliary tract cancer and their prognostic significance
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Krukenberg Tumor Related to Gallbladder Cancer in a Young Woman: A Case Report and Review of the Literature
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Design, synthesis and evaluation of 4,7-disubstituted 8-methoxyquinazoline derivatives as potential cytotoxic agents targeting β-catenin/TCF4 signaling pathway
Kaushik Neogi, Prashant R. Murumkar, Priyanshu Sharma, Poonam Yadav, Mallika Tewari, Devarajan Karunagaran, Prasanta Kumar Nayak, Mange Ram Yadav
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Yeseul Kim, Seong Sik Bang, Seungyun Jee, Sungeon Park, Su-Jin Shin, Kiseok Jang
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Overexpression of c-met Protein in Gastric Cancer and Role of uPAR as a Therapeutic Target: Hyun A Oh, Gu Lee, Hee Jung Kang, Yong Gil Kim, Sung Hwa Bae, Jae Lyun Lee, Kyung Hee Lee, Myung Soo Hyun, Dong Suk Kim; Cancer Res Treat. 2003;35(1):9-15. Published online February 28, 2003; DOI: https://doi.org/10.4143/crt.2003.35.1.9

Abstract PDF

PURPOSE
One of the members of the tyrosine kinase receptor family is the protein product of the c-met proto-oncogene, which is the receptor for hepatocyte growth factor (HGF). HGF is known as a potent mitogen and motogen for many kinds of carcinoma cells, and has been found to simulate the growth and progression of gastric cancer cells through HGF-receptors. In addition, the urokinase-type plasminogen activator (uPA) and receptor (uPAR) also play important roles in the invasion and metastasis. MATERIALS AND METHODS: The expression of c-met protein was investigated using immunohistochemical staining of 50 paraffin embedded gastric cancers, and by measuring the serum uPAR levels, before and after an operation, in gastric cancer patients using an ELISA assay. RESULTS: Of the 50 cases, 32 (64%) expressed the c-met protein. The c-met protein expression was significantly correlated with the TNM staging (p<0.05), but the other prognostic factors were not significant variables. According to a Kaplan-Meier's plot, the one and three year overall survival rates were 94 and 70% in patients not expressing the c-met protein, and 81 and 33% in those that did, and the Survival curves revealed a significantly different prognosis (p=0.04). Elevated serum uPAR levels (> or=3257.8 pg/ml, control+/-mean 2SD) were observed in 9 (34.6%) of 26 gastric cancer patients, but in none of control subjects. Average serum uPAR levels were 2980.8+/-616.2 pg/ml before the operation and 2404.7+/-455.9 pg/ml after, and decreased significantly after surgical resection (p<0.05). The serum uPAR level correlated significantly with lymph node metastasis and vessel invasion (p<0.05) CONCLUSION: The expression of c-met protein, and the level of uPAR, may be prognostic factors in gastric cancer.

Citations

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Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer
Lan-Mei Wang, Wei-Wei Zhang, Ying-Yang Qiu, Fang Wang
World Journal of Gastrointestinal Oncology.2024; 16(6): 2781. CrossRef
Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review
Wu-Jie Wei, Ya-Li Hong, Yi Deng, Guan-Liang Wang, Jiang-Tao Qiu, Fang Pan
World Journal of Gastrointestinal Oncology.2024; 16(8): 3397. CrossRef
Human Triosephosphate Isomerase Is a Potential Target in Cancer Due to Commonly Occurring Post-Translational Modifications
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SMYD3 Modulates the HGF/MET Signaling Pathway in Gastric Cancer
Katia De Marco, Martina Lepore Signorile, Elisabetta Di Nicola, Paola Sanese, Candida Fasano, Giovanna Forte, Vittoria Disciglio, Antonino Pantaleo, Greta Varchi, Alberto Del Rio, Valentina Grossi, Cristiano Simone
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MET in gastric cancer with liver metastasis: The relationship between MET amplification and Met overexpression in primary stomach tumors and liver metastasis
Han S. Kim, Hong J. Chon, Hyunki Kim, Su‐Jin Shin, Volker Wacheck, Aaron M. Gruver, Jong S. Kim, Sun Y. Rha, Hyun C. Chung
Journal of Surgical Oncology.2018; 117(8): 1679. CrossRef
Hepatocyte growth factor induced up-regulations of VEGF through Egr-1 in hepatocellular carcinoma cells
Kyung Hee Lee, Jae-Ryong Kim
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Association of Extracellular Cleavage of E-Cadherin Mediated by MMP-7 with HGF-Induced in vitro Invasion in Human Stomach Cancer Cells
K.H. Lee, E.Y. Choi, M.S. Hyun, B.I. Jang, T.N. Kim, S.W. Kim, S.K. Song, J.H. Kim, J.-R. Kim
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Effect of Hepatocyte Growth Factor on the Expression of E-cadherin in Gastric Carcinoma Cell Lines: Sang Uk Han, Won Hung Lee, Wook Hwan Kim, Myung Wook Kim, Jae Ho Lee, Sang Yong Song, Kuhn Uk Lee; J Korean Cancer Assoc. 2000;32(5):852-862.

Abstract PDF: PURPOSE
Previously, we reported that the expression of E-cadherin was significantly decreased according to the increase of the level of hepatocyte growth factor (HGF) in gastric cancer tissue. In this work, the effect of HGF on the cell-cell adhesion and intracellular distribution of E-cadherin in the gastric carcinoma cell lines were studied. MATERIALS AND METHODS: Western blot analysis was performed to confirm the presence or abscence of c-Met and E-cadherin in SNU-1, 5, and 16 cells. Tyrosine phosphorylation of c-Met, E-cadherin, alpha-, beta-, gamma-catenins was checked by immunoprecipitation. The morphologic changes induced by HGF were studied with immunocytochemical staining. Functional proportion of E-cadherin was estimated by cell fractionation. The effect of HGF on cell proliferation and invasion was also assessed.
RESULTS
Among SNU-1, 5, and 16 cell lines, only SNU-16 cells expressed both E-cadherin and c-Met. A morphological change from epithelial shape to fibroblastic one was observed in the SNU-16 cells after treatment with HGF. In addition, E-cadherin expression of the SNU-16 cells was shifted from the membrane and to the cytoplasm, and the functional fraction of E-cadherin was decreased in the SNU-16 cells treated with HGF. On the other hand, HGF increased the proliferation and invasion of the SNU-16 cells.
CONCLUSION
These results suggest that HGF may regulate cell adhesion in gastric carcinomas via the cellular redistribution and functional change of E-cadherin.

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