An Adaptive Src-PDGFRA-Raf Axis in Rhabdomyosarcoma

Biochem Biophys Res Commun. 2012 Sep 28;426(3):363-8. doi: 10.1016/j.bbrc.2012.08.092. Epub 2012 Aug 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzamides
  • Benzenesulfonates / pharmacology
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Imatinib Mesylate
  • Mice
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Rhabdomyosarcoma, Alveolar / enzymology*
  • Rhabdomyosarcoma, Alveolar / pathology*
  • Sorafenib
  • Tumor Cells, Cultured
  • raf Kinases / metabolism*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • AG 1879
  • Benzamides
  • Benzenesulfonates
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Niacinamide
  • Imatinib Mesylate
  • Sorafenib
  • Receptor, Platelet-Derived Growth Factor alpha
  • src-Family Kinases
  • raf Kinases