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

• Published in: Anticancer research Vol. 41; no. 10; pp. 4807 - 4820
• Main Authors: Son, Kyoung-Hwa, Kim, Min-Young, Shin, Jung-Young, Kim, Jeong-Oh, Kang, Jin-Hyoung
• Format: Journal Article
• Language: English
• Published: Athens International Institute of Anticancer Research 01.10.2021
• Subjects: Adenocarcinoma; Anticancer properties; Antitumor activity; Apoptosis; Biocompatibility; Cell death; Cell growth; Cell proliferation; Cyclin-dependent kinase 4; Cytotoxicity; Drug delivery; Flow cytometry; In vitro methods and tests; In vivo methods and tests; Inhibitors; K-Ras protein; Lung cancer; Mutation; Paclitaxel; Synergistic effect; Toxicity; Tubulin; Western blotting; Xenografts; Xenotransplantation
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.15296

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.