Abstract IA08: Epigenetic mechanisms of resistance to targeted therapy

Abstract

Abstract Targeted cancer therapies, such as inhibitors of the ALK receptor tyrosine kinase, have yielded promising outcomes in patients whose tumors aberrantly express ALK, yet the development of resistance invariably limits their efficacy. To address this issue, we have investigated potential mechanisms of resistance to ALK inhibitors in neuroblastoma cells expressing ALK point mutations. In tumor cells expressing the ALKF1174L mutant kinase in the absence of MYCN amplification, we observed that resistance to ALK inhibitors develops through activation of MAPK signaling and induction of epithelial-to-mesenchymal transition. By contrast, in tumor cells expressing the same mutation but with concomitant MYCN overexpression due to genomic amplification, resistance arises through a different mechanism, characterized by extensive chromatin remodeling and conversion to a stem cell-like state. I will describe our latest insights into the molecular details underlying this latter mechanism with emphasis on transcriptional regulators. Citation Format: Rani E. George. Epigenetic mechanisms of resistance to targeted therapy [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA08.