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MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer
Shrey Ramesh1, Ahmet Cifci1, Saahil Javeri1
1Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
Purpose:
The objective of this study was to investigate the effects of inhibiting the MET receptor with capmatinib, a potent and clinically relevant ATP-competitive tyrosine kinase inhibitor, in combination with radiation in MET exon 14-mutated and MET-amplified non-small cell lung (NSCLC) cancer models.
Methods And Materials:
In vitro effects of capmatinib and radiation on cell proliferation, colony formation, MET signaling, apoptosis, and DNA damage repair were evaluated. In vivo tumor responses were assessed in cell line xenograft and patient-derived xenograft models. Immunohistochemistry (IHC) was used to confirm in vitro results.
Results:
In vitro clonogenic survival assays demonstrated radiosensitization with capmatinib in both MET exon 14-mutated and MET-amplified NSCLC cell lines. No radiation-enhancing effect was observed in MET wild-type NSCLC and human bronchial epithelial cell line. Minimal apoptosis was detected with the combination of capmatinib and radiation. Capmatinib plus radiation compared to radiation alone resulted in inhibition of DNA double-strand break repair as measured by prolonged expression of γH2AX. In vivo, the combination of capmatinib and radiation significantly delayed tumor growth compared to vehicle control, capmatinib alone, or radiation alone. IHC indicated inhibition of phospho-MET and phospho-S6 and a decrease in Ki67 with inhibition of MET.
Conclusions:
Inhibition of MET with capmatinib enhanced the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.
Insights
Capmatinib, a MET inhibitor, enhances radiation therapy in non-small cell lung cancer (NSCLC) with MET alterations. This combination therapy inhibits tumor growth and DNA repair more effectively than radiation alone.
Area of Science:
- Oncology
- Molecular Biology
- Radiation Oncology
Background:
- Non-small cell lung cancer (NSCLC) with MET exon 14 mutations or amplification presents therapeutic challenges.
- Targeting the MET receptor tyrosine kinase is a strategy for NSCLC treatment.
- Capmatinib is an ATP-competitive inhibitor of the MET receptor.
Approach:
- Investigated the combination of capmatinib and radiation in MET-altered NSCLC models.
- Assessed in vitro effects on cell proliferation, colony formation, MET signaling, apoptosis, and DNA repair.
- Evaluated in vivo tumor responses using xenograft models and confirmed findings with immunohistochemistry (IHC).
Key Points:
- Capmatinib demonstrated radiosensitization in MET-mutated and amplified NSCLC cell lines.
- The combination inhibited DNA double-strand break repair, indicated by prolonged γH2AX expression.
- In vivo, capmatinib plus radiation significantly delayed tumor growth compared to monotherapy or control.
Conclusions:
- Inhibition of MET with capmatinib enhances radiation efficacy in MET-altered NSCLC.
- The combination therapy shows promise for treating specific NSCLC subtypes.
- Further research into MET-targeted combinations is warranted.
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