Oncotarget

Research Papers:

PDGFRα up-regulation mediated by Sonic Hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation

Francesco Sabbatino, Yangyang Wang, Xinhui Wang, Keith T. Flaherty, Ling Yu, David Pepin, Giosue’ Scognamiglio, Stefano Pepe, John M. Kirkwood, Zachary A. Cooper, Dennie T. Frederick, Jennifer A. Wargo, Soldano Ferrone _ and Cristina R. Ferrone

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Oncotarget. 2014; 5:1926-1941. https://doi.org/10.18632/oncotarget.1878

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Abstract

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

Correspondence:

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

Abstract

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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