Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
Int J Radiat Oncol Biol Phys. 2024 Apr 1;118(5):1379-1390. doi: 10.1016/j.ijrobp.2023.11.013. Epub 2023 Nov 16.
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.
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.
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.
Inhibition of MET with capmatinib enhances the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.
本研究旨在探讨 MET 受体抑制剂卡马替尼与放射治疗联合应用对 MET 外显子 14 突变和 MET 扩增的非小细胞肺癌（NSCLC）模型的影响。
评估卡马替尼和放射治疗对细胞增殖、集落形成、MET 信号转导、细胞凋亡和 DNA 损伤修复的体外作用。在细胞系异种移植和患者来源的异种移植模型中评估体内肿瘤反应。免疫组化用于验证体外结果。
体外集落形成存活实验表明，卡马替尼在 MET 外显子 14 突变和 MET 扩增的 NSCLC 细胞系中具有放射增敏作用。在 MET 野生型 NSCLC 和人支气管上皮细胞系中未观察到放射增强作用。联合应用卡马替尼和放射治疗后，检测到的细胞凋亡很少。与单独放射治疗相比，卡马替尼联合放射治疗导致 DNA 双链断裂修复抑制，表现为 γH2AX 的表达延长。在体内，与单独使用载体对照、卡马替尼或放射治疗相比，卡马替尼联合放射治疗显著延迟肿瘤生长。免疫组化显示抑制磷酸化 MET 和磷酸化 S6，并降低 Ki67，提示 MET 抑制。
MET 抑制剂卡马替尼抑制 MET 可增强 MET 外显子 14 突变和 MET 扩增的 NSCLC 模型中放射治疗的效果。
