Abstract 4407: Targeting BMP4 and miR-139-5p in EGFR-mutant non-small cell lung cancer cells

Abstract

Abstract Non-small cell lung cancer (NSCLC) cells with harboring EGF receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recent studies suggest that bone morphogenetic proteins (BMPs) and microRNAs (miRNAs) might act as oncogenes or suppressors in tumor microenvironment. We identified the potential roles of BMPs and miRNAs involved in EGFR TKIs resistance by analyzing datasets from a pair of NSCLC-sensitive and NSCLC-resistant cells. BMP4 was found to be significantly over-expressed in EGFR-TKI resistant cells and its underlying mechanism was highly associated with induction of energy metabolism for cancer cells through modulating Acyl-CoA synthetase long-chain family member 4. In addition, miR-139-5p was found to be importantly down-regulated in the resistant NSCLC cells. The combination of miR-139-5p and yuanhuadine, a natural product-derived antitumor agent, synergistically suppressed the BMP4 expression in the resistant cells. We furthermore confirmed that LDN-193189, a small molecule BMP receptor 1 inhibitor inhibited the tumor growth in a xenograft nude mouse model implanted with drug resistant cells. These findings suggest a role of BMP4-mediated tumorigenesis in the progression of acquired drug resistance in EGFR-mutant NSCLC cells. Key words: microRNAs, bone morphogenetic proteins, drug resistance, metabolism, EGFR-TKIs, NSCLC. Acknowledgements This study was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A02062012). Citation Format: Duc-Hiep Bach, Thi-Thu-Trang Luu, Dong-Hwa Kim, Yong Jin An, Hyen Joo Park, Sunghyouk Park, Sang Kook Lee. Targeting BMP4 and miR-139-5p in EGFR-mutant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4407.