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Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy
Jin-Soo Kim1, Mi Young Kim1, Sungyoul Hong2
1Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea.
Abstract:
Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.
Insights
MET inhibitors capmatinib and savolitinib effectively suppressed MET-amplified gastric cancer cell growth. These MET inhibitors also showed synergistic effects with trastuzumab in HER2- and MET-amplified gastric cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- MET proto-oncogene receptor tyrosine kinase amplification is implicated in various cancers.
- MET inhibitors like capmatinib and savolitinib are approved for treating certain MET-driven malignancies.
- Gastric cancer (GC) with MET amplification represents a potential therapeutic target.
Purpose of the Study:
- To investigate the efficacy of MET inhibitors (capmatinib and savolitinib) in MET-amplified gastric cancer (GC) cells.
- To evaluate the impact of these inhibitors on MET signaling pathways.
- To assess the combination therapy of MET inhibitors with trastuzumab in relevant GC models.
Main Methods:
- Screening of 37 GC cell lines to identify MET-amplified lines (copy number >10).
- Cytotoxicity and clonogenic assays to assess anti-proliferative effects of capmatinib and savolitinib.
- Western blotting to analyze MET signaling pathway inhibition (MET, AKT, ERK).
- In vivo xenograft studies using MKN-45 cells to evaluate therapeutic efficacy.
- Combination studies with trastuzumab in HER2- and MET-positive OE33 cells.
Main Results:
- Four GC cell lines (SNU-620, ESO51, MKN-45, SNU-5) and OE33 cells were identified as MET-positive with high copy numbers.
- Capmatinib and savolitinib demonstrated dose-dependent anti-proliferative and cytotoxic effects on MET-amplified GC cells.
- Savolitinib inhibited MET phosphorylation and downstream AKT and ERK signaling.
- Savolitinib reduced colony formation in soft agar and showed anti-tumor activity in vivo.
- Combination of trastuzumab and capmatinib enhanced inhibition of AKT and ERK in HER2- and MET-positive cells.
Conclusions:
- Targeting MET with savolitinib and capmatinib is a viable strategy for suppressing MET-amplified GC growth.
- MET inhibitors exhibit synergistic effects with trastuzumab in GC cells co-amplifying MET and HER2.
- These findings support further investigation of MET-targeted therapies, alone or in combination, for specific GC subtypes.
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