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An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma.

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.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Abraham J,Chua YX,Glover JM,Tyner JW,Loriaux MM,Kilcoyne A,Giles FJ,Nelon LD,Carew JS,Ouyang Y,Michalek JE,Pal R,Druker BJ,Rubin BP,Keller C

doi

10.1016/j.bbrc.2012.08.092

subject

Has Abstract

pub_date

2012-09-28 00:00:00

pages

363-8

issue

3

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(12)01658-0

journal_volume

426

pub_type

杂志文章

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