Abstract 3703: PDGFRα up-regulation mediated by Sonic Hedgehog Pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation

Abstract

Abstract Control of mutant BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Up-regulation of growth factor receptor such as platelet-derived growth factor receptor (PDGFR)β or insulin-like growth factor receptor (IGFR) is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that up-regulation of PDGFRα, a growth factor receptor which markedly differs in its functional properties from its family member PDGFRβ, causes BRAF-I resistance in vitro and in vivo. PDGFRα inhibition by PDGFRα-specific short hairpin RNA (shRNAs) and by clinically available PDGFRα inhibitors (sunitinib, imatinib and crenolanib) restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. This effect reflects the inhibition of ERK and AKT activation which is associated with BRAF-I resistance of melanoma cells. PDGFRα up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRα inhibition, Shh inhibition by the novel small molecule LDE225 restores and increases melanoma cells' sensitivity to BRAF-I in vitro and in vivo. These effects are mediated by PDGFRα down-regulation and by inhibition of ERK and AKT activation. The clinical relevance of these data is indicated by the association of PDGFRα up-regulation in melanoma matched biopsies of BRAF-I +/- MEK inhibitor treated patients with shorter time to disease progression and less tumor regression. These findings suggest that monitoring patients for early PDGFRα up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRα or Shh inhibitors Citation Format: Francesco Sabbatino, Yangyang Wang, Xinhui Wang, Keith T. Flaherty, David Pepin, Giosuè Scognamiglio, Ling Yu, Zachary A. Cooper, Stefano Pepe, John M. Kirkwood, Dennie T. Frederick, Jennifer A. Wargo, Soldano Ferrone, Cristina R. Ferrone. PDGFRα up-regulation mediated by Sonic Hedgehog Pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2014-3703