AI Article Synopsis
- The study aimed to explore how capmatinib, a MET receptor inhibitor, enhances the effectiveness of radiation therapy in non-small cell lung cancer (NSCLC) models with specific MET mutations.
- In laboratory tests, capmatinib showed a significant increase in cancer cell sensitivity to radiation, particularly in cell lines with MET exon 14 mutations or MET amplification, while non-mutated cells did not exhibit this effect.
- The results indicate that combining capmatinib and radiation not only inhibited tumor growth in animal models but also impaired DNA damage repair mechanisms, suggesting a potential new treatment strategy for certain NSCLC patients.
Article Abstract
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 was used to confirm the 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 a human bronchial epithelial cell line. Minimal apoptosis was detected with the combination of capmatinib and radiation. Capmatinib plus radiation compared with 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 with vehicle control, capmatinib alone, or radiation alone. Immunohistochemistry indicated inhibition of phospho-MET and phospho-S6 and a decrease in Ki67 with inhibition of MET.
Conclusions: Inhibition of MET with capmatinib enhances the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.
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| http://dx.doi.org/10.1016/j.ijrobp.2023.11.013 | DOI Listing |
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