An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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

Fingerprint

Alveolar Rhabdomyosarcoma
Rhabdomyosarcoma
Tumors
Cell culture
Primary Cell Culture
Neoplasms
Cell Survival
Cells
src-Family Kinases
Cell growth
Sarcoma
Young Adult
Phosphotransferases
Molecules
Growth

Keywords

  • Imatinib
  • Pdgfra
  • Receptor tyrosine kinase
  • Sorafenib

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma. / Abraham, Jinu; Chua, Ying Xuan; Glover, Jason M.; Tyner, Jeffrey; Loriaux, Marc; Kilcoyne, Aoife; Giles, Francis J.; Nelon, Laura D.; Carew, Jennifer S.; Ouyang, Yongjian; Michalek, Joel E.; Pal, Ranadip; Druker, Brian; Rubin, Brian P.; Keller, Charles.

In: Biochemical and Biophysical Research Communications, Vol. 426, No. 3, 28.09.2012, p. 363-368.

Research output: Contribution to journalArticle

Abraham, J, Chua, YX, Glover, JM, Tyner, J, Loriaux, M, Kilcoyne, A, Giles, FJ, Nelon, LD, Carew, JS, Ouyang, Y, Michalek, JE, Pal, R, Druker, B, Rubin, BP & Keller, C 2012, 'An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma', Biochemical and Biophysical Research Communications, vol. 426, no. 3, pp. 363-368. https://doi.org/10.1016/j.bbrc.2012.08.092
Abraham, Jinu ; Chua, Ying Xuan ; Glover, Jason M. ; Tyner, Jeffrey ; Loriaux, Marc ; Kilcoyne, Aoife ; Giles, Francis J. ; Nelon, Laura D. ; Carew, Jennifer S. ; Ouyang, Yongjian ; Michalek, Joel E. ; Pal, Ranadip ; Druker, Brian ; Rubin, Brian P. ; Keller, Charles. / An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma. In: Biochemical and Biophysical Research Communications. 2012 ; Vol. 426, No. 3. pp. 363-368.
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