title: 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.
authors.affiliation: Pediatric Cancer Biology Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA. abraham@ohsu.edu
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.forename: Ying Xuan
authors.initials: YX
authors.lastname: Chua
authors.forename: Jason M
authors.initials: JM
authors.lastname: Glover
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.forename: Aoife
authors.initials: A
authors.lastname: Kilcoyne
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Laura D
authors.initials: LD
authors.lastname: Nelon
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.forename: Ranadip
authors.initials: R
authors.lastname: Pal
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D000068877:Imatinib Mesylate; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018232:Rhabdomyosarcoma, Alveolar / Q000201:enzymology* / Q000473:pathology*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D048490:raf Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D001549:Benzamides; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D020796:Receptor, Platelet-Derived Growth Factor alpha; D019061:src-Family Kinases; D048490:raf Kinases