An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma

Jinu Abraham, Ying Xuan Chua, Jason M. Glover, Jeffrey W. Tyner, Marc M. Loriaux, Aoife Kilcoyne, Francis J. Giles, Laura D. Nelon, Jennifer S. Carew, Yongjian Ouyang, Joel E. Michalek, Ranadip Pal, Brian J. Druker, Brian P. Rubin, Charles Keller

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Alveolar rhabdomyosarcoma (aRMS) is a very aggressive sarcoma of children and young adults. Our previous studies have shown that small molecule inhibition of Pdgfra is initially very effective in an aRMS mouse model. However, slowly evolving, acquired resistance to a narrow-spectrum kinase inhibitor (imatinib) was common. We identified Src family kinases (SFKs) to be potentiators of Pdgfra in murine aRMS primary cell cultures from mouse tumors with evolved resistance in vivo in comparison to untreated cultures. Treating the resistant primary cell cultures with a combination of Pdgfra and Src inhibitors had a strong additive effect on cell viability. In Pdgfra knockout tumors, however, the Src inhibitor had no effect on tumor cell viability. Sorafenib, whose targets include not only PDGFRA but also the Src downstream target Raf, was effective at inhibiting mouse and human tumor cell growth and halted progression of mouse aRMS tumors in vivo. These results suggest that an adaptive Src-Pdgfra-Raf-Mapk axis is relevant to PDGFRA inhibition in rhabdomyosarcoma.

Original languageEnglish (US)
Pages (from-to)363-368
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume426
Issue number3
DOIs
StatePublished - Sep 28 2012

Keywords

  • Imatinib
  • Pdgfra
  • Receptor tyrosine kinase
  • Sorafenib

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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