An adaptive Src-PDGFRA-Raf axis in rhabdomyosarcoma

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• 作者：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
• 关键词：Imatinib ; Sorafenib ; Receptor tyrosine kinase ; Pdgfra
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 出版时间：28 September, 2012
• 年：2012
• 卷：426
• 期：3
• 页码：363-368
• 全文大小：826 K

文摘

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.