Abstract 2284: Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR

Background: Standard second-line chemotherapy against advanced non-small-cell lung cancer (NSCLC) is a single agent such as docetaxel, pemetrexed, or erlotinib (Erl). We recently reported that the combination of amrubicin (AMR) and Erl was clinically safe and effective for previously treated NSCLC patients. The purpose of this research is to confirm the experimental effectiveness of the combination and to investigate mechanism of the action. Methods: We perform to evaluate the NSCLC cell lines proliferation inhibition by using XTT assay and to make two-dimension isobolograms for assessment of the combination effect. Flowcytemetry analysis (FACS) and Western blot analysis (WB) is also done in vitro. In vivo growth inhibition assay using subcutaneous model on SCID mice is performed. In addition, we measure intracellular concentration of amrubicinol(AMR-OH) which is converted as active metabolite from AMR in both cells treated with AMR alone and the combination. Results: The combination of AMR and Erl had significant synergistic effect on EGFR wild type NSCLC cell line A549, while additive effect on EGFR mutant cell line PC-9. Sub G0-G1 population on FACS was significantly increased in A549 cells treated with combination. The combination activated apoptosis related proteins in WB. The strong growth inhibition of subcutaneous tumors on SCID mice was observed in the combination cohort. Intracellular concentration of AMR-OH was significantly increased in the combination than in AMR monotherapy. Conclusion: The combination of AMR and Erl is synergistically induced apoptosis and growth inhibition on A549 cells via increasing intracellular concentration of AMR-OH. This combination may be a promising therapeutic option against advanced NSCLC with wild type EGFR. Citation Format: Sakiko Otani, Jiichiro Sasaki, Kuniko Masuda, Kazuya Okamoto, Akiko Namubu, Toshihide Matsumoto, Masumi Tanaka, Mikiko Ishihara, Yoshiro Nakahara, Tomoya Fukui, Satoshi Igawa, Noriyuki Masuda. Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2284.