Abemaciclib, a Selective CDK4/6 Inhibitor Enhances the Radiosensitivity of Non-Small Cell Lung Cancer in vitro and in vivo

Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of CDK4/6 inhibitor, Abemaciclib in Non-Small Cell Lung Cancer cells (NSCLC) in vitro and in vivo. Experimental Design: IR enhancement by Abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by -H2AX analysis. Global metabolic alterations by Abemaciclib and IR combination was evaluated by LC/MS mass spectrometry and YSI-Bioanalyzer. Effects of Abemaciclib and IR combination in vivo was studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry. Results: Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. Post-IR, Abemaciclib treatment inhibited DNA damage repair as measured by -H2AX. Mechanistically, Abemaciclib inhibited RB phosphorylation leading to cell cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pool causing nutrient stress. In vivo, Abemaciclib when administered in an adjuvant setting for the second week post-fractionated IR further inhibited vasculogenesis and tumor re-growth with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting CDK4/6 pathway by Abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC. Conclusions:Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker driven combination therapeutic strategy for patients with NSCLC.

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