Sabbatino, FrancescoWang, YangYangWang, XinhuiFlaherty, KeithYu, LingPepin, DavidScognamiglio, Giosue'Pepe, StefanoKirkwood, John M.Cooper, Zachary A.Frederick, Dennie T.Wargo, Jennifer AnnFerrone, SoldanoFerrone, Cristina2014-07-072014Sabbatino, F., Y. Wang, X. Wang, K. T. Flaherty, L. Yu, D. Pepin, G. Scognamiglio, et al. 2014. “PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation.” Oncotarget 5 (7): 1926-1941.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406784Control of BRAF(V600E) metastatic melanoma by BRAF inhibitor (BRAF-I) is limited by intrinsic and acquired resistance. Growth factor receptor up-regulation is among the mechanisms underlying BRAF-I resistance of melanoma cells. Here we demonstrate for the first time that PDGFRα up-regulation causes BRAF-I resistance. PDGFRα inhibition by PDGFRα-specific short hairpin (sh)RNA and by PDGFRα inhibitors 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 LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRα down-regulation and by ERK and AKT inhibition. 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.en-USBRAF inhibitor resistancePDGFRα up-regulationPDGFRα inhibitorsmelanomasonic hedgehog pathwayLDE225Journal Article2014-07-0710.18632/oncotarget.1878