PDGFRα up-regulation mediated by Sonic Hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation
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Francesco Sabbatino1,3,4,*, Yangyang Wang1,3,*, Xinhui Wang1,3, Keith T. Flaherty2,3, Ling Yu5,7, David Pepin1,3, Giosue’ Scognamiglio5,8, Stefano Pepe4,10, John M. Kirkwood6, Zachary A. Cooper1,3,9, Dennie T. Frederick1,3, Jennifer A. Wargo1,3,9, Soldano Ferrone1,3, Cristina R. Ferrone1,3
1 Department of Surgery, Massachusetts General Hospital, Boston, MA
2 Department of Medical Oncology, Massachusetts General Hospital, Boston, MA
3 Harvard Medical School, Boston, MA
4 Department of Clinical and Molecular Oncology and Endocrinology, University of Naples “Federico II”, Naples, Italy
5 Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pittsburgh, PA
6 Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pittsburgh, PA
7 Institute for Clean Energy & Advanced Materials, Southwest University, Chongqing, P.R. China
8 Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy
9 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
10 Department of Medicine, University of Salerno, Salerno, Italy
* These authors contributed equally to this work
Soldano Ferrone, email:
Keywords: BRAF inhibitor resistance, PDGFRα up-regulation, PDGFRα inhibitors, melanoma, sonic hedgehog pathway, LDE225.
Received: February 13, 2014 Accepted: March 31, 2014 Published: March 31, 2014
Control 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.
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