Synergistic Antitumor Effect of Taxanes and CDK4/6 Inhibitor in Lung Cancer Cells and Mice Harboring KRAS Mutations

Abstract

Background/aim: LY2835219 (LY), a novel CDK4/6 inhibitor, prevents cell proliferation through G1 arrest. Docetaxel (DTX) and paclitaxel (PTX) are cytotoxic drugs targeting tubulin-mediated apoptotic cell death via G2/M arrest. We evaluated the antitumor effects of DTX/PTX and LY individually and in combination in lung adenocarcinoma cells with or without KRAS mutations and xenograft mice harboring KRAS mutations.

Materials and methods: We investigated in vitro/in vivo changes in signaling molecules and analyzed cell proliferation, cycle, and apoptosis via flow cytometry and western blotting.

Results: LY cytotoxicity was dose-dependent and varied with KRAS mutation status. DTX→LY showed synergistic cytotoxicity regardless of KRAS mutation. Furthermore, the synergistic effect of PTX→LY was significantly greater than that of PTX+LY. DTX→LY remarkably reduced the number of G0/G1 cells and increased the number of G2/M arrested cells, resulting in an increase in apoptosis and subG1 cells.

Conclusion: DTX→LY has synergistic antitumor effect in lung cancer cells and xenograft mice regardless of KRAS mutation.

Keywords: CDK4/6 inhibitor; Docetaxel; KRAS mutation; lung cancer; paclitaxel; synergism.