Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non–Small Cell Lung Cancer In Vitro and In Vivo

摘要: Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of CDK4/6 inhibitor abemaciclib in non-small cell lung cancer (NSCLC) cells vitro vivoExperimental Design: IR enhancement by a variety NSCLC lines was assessed clonogenic assay, flow cytometry, target inhibition verified immunoblotting. IR-induced DNA damage repair evaluated γH2AX analysis. Global metabolic alterations combination were LC/MS mass spectrometry YSI bioanalyzer. Effects vivo studied xenograft tumor regrowth delay, lysate immunoblotting, tissue section immunohistochemistry.Results: Abemaciclib enhanced radiosensitivity independent RAS or EGFR status. Enhancement lost deficient for functional p53 RB protein. After IR, treatment inhibited as measured γH2AX. Mechanistically, phosphorylation, leading to cell-cycle arrest. It also mTOR signaling reduced intracellular amino acid pools, causing nutrient stress. In vivo, abemaciclib, when administered an adjuvant setting second week after fractionated further vasculogenesis regrowth, with sustained RB/E2F activity, pathway, HIF-1 expression. summary, our study signifies inhibiting pathway promising therapeutic strategy treat NSCLC.Conclusions: enhances preclinical models, potentially providing novel biomarker-driven patients NSCLC. Clin Cancer Res; 24(16); 3994-4005. ©2018 AACR.