PDGFRa 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, Cristina R. Ferrone

Research output: Contribution to journalArticle

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 PDGFRa up-regulation causes BRAF-I resistance. PDGFRa inhibition by PDGFRa-specific short hairpin (sh)RNA and by PDGFRa 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. PDGFRa up-regulation is mediated by Sonic Hedgehog Homolog (Shh) pathway activation which is induced by BRAF-I treatment. Similarly to PDGFRa inhibition, Shh inhibition by LDE225 restores and increases melanoma cells' sensitivity to BRAF-I. These effects are mediated by PDGFRa down-regulation and by ERK and AKT inhibition. The clinical relevance of these data is indicated by the association of PDGFRa 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 PDGFRa up-regulation will facilitate the identification of those who may benefit from the treatment with BRAF-I in combination with clinically approved PDGFRa or Shh inhibitors.

Original languageEnglish
Pages (from-to)1926-1941
Number of pages16
JournalOncotarget
Volume5
Issue number7
Publication statusPublished - 2014

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Keywords

  • BRAF inhibitor resistance
  • LDE225
  • Melanoma
  • PDGFRa inhibitors
  • PDGFRa up-regulation
  • Sonic hedgehog pathway

ASJC Scopus subject areas

  • Oncology

Cite this

Sabbatino, F., Wang, Y., Wang, X., Flaherty, K. T., Yu, L., Pepin, D., Scognamiglio, G., Pepe, S., Kirkwood, J. M., Cooper, Z. A., Frederick, D. T., Wargo, J. A., Ferrone, S., & Ferrone, C. R. (2014). PDGFRa up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget, 5(7), 1926-1941.