MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer.

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.

MET Inhibitor Capmatinib Radiosensitizes MET Exon 14-Mutated and MET-Amplified Non-Small Cell Lung Cancer.

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.

Biological Characterization of the Effects of Filtration on the Xoft Axxent® Electronic Brachytherapy Source for Cervical Cancer Applications.

Low-energy X-ray sources that operate in the kilovoltage energy range have been shown to induce more cellular damage when compared to their megavoltage counterparts. However, low-energy X-ray sources are more susceptible to the effects of filtration on the beam spectrum. This work sought to characterize the biological effects of the Xoft Axxent® source, a low-energy therapeutic X-ray source, both with and without the titanium vaginal applicator in place. It was hypothesized that there would be an increase in relative biological effectiveness (RBE) of the Axxent® source compared to 60Co and that the source in the titanium vaginal applicator (SIA) would have decreased biological effects compared to the bare source (BS). This hypothesis was drawn from linear energy transfer (LET) simulations performed using the TOPAS Monte Carlo user code as well a reduction in dose rate of the SIA compared to the BS. A HeLa cell line was maintained and used to evaluate these effects. Clonogenic survival assays were performed to evaluate differences in the RBE between the BS and SIA using 60Co as the reference beam quality. Neutral comet assay was used to assess induction of DNA strand damage by each beam to estimate differences in RBE. Quantification of mitotic errors was used to evaluate differences in chromosomal instability (CIN) induced by the three beam qualities. The BS was responsible for the greatest quantity of cell death due to a greater number of DNA double strand breaks (DSB) and CIN observed in the cells. The differences observed in the BS and SIA surviving fractions and RBE values were consistent with the 13% difference in LET as well as the factor of 3.5 reduction in dose rate of the SIA. Results from the comet and CIN assays were consistent with these results as well. The use of the titanium applicator results in a reduction in the biological effects observed with these sources, but still provides an advantage over megavoltage beam qualities. © 2023 by Radiation Research Society.