Abstract 2681: Stromal neuregulin-1 promotes adaptive resistance in mutant BRAF melanoma

Abstract

Abstract RAF inhibitors are first-line treatments for melanomas that harbor BRAF V600E/K mutations; however, patients invariably progress on these targeted therapies. While durable resistance is mediated frequently by stable alterations intrinsic to the tumor cells leading to ERK1/2 pathway reactivation, the compensatory activation of growth factor receptor tyrosine kinases (RTKs) modulates the level of initial response. The composition of the tumor microenvironment likely plays a key role in these compensatory/adaptive responses to targeted inhibitors. In this study, we demonstrate that NRG1 is expressed in fibroblasts, as well as cancer associated fibroblasts (CAFs) isolated from a mutant BRAF melanoma. Fibroblast derived-NRG1 was able to mediate the enhanced ErbB3 pathway activation in RAF-inhibited mutant BRAF melanoma cells. Furthermore, conditioned medium from fibroblasts and CAFs limits RAF inhibitor cytotoxicity in V600 BRAF-harboring melanomas. Importantly, ErbB3 and ErbB2 targeting antibodies partially reverse the protective effects of fibroblast-derived medium on ErbB3 pathway activation and cell growth properties of mutant BRAF-inhibited melanoma cells. Together, these data demonstrate a requirement for a paracrine-produced factor in the tumor microenvironment to promote resistance to RAF inhibitor in mutant BRAF melanoma and reinforce the idea that targeting ErbB3/ErbB2 signaling may improve the efficacy of RAF inhibitors. Citation Format: Claudia Capparelli, Sheera Rosenbaum, Adam Berger, Andrew E. Aplin. Stromal neuregulin-1 promotes adaptive resistance in mutant BRAF melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2681. doi:10.1158/1538-7445.AM2015-2681