Imatinib and dasatinib inhibit hemangiosarcoma and implicate PDGFR-β and Src in tumor growth

Erin B. Dickerson, Kevin Marley, Wade Edris, Jeffrey W. Tyner, Vidya Schalk, Valerie MacDonald, Marc Loriaux, Brian J. Druker, Stuart C. Helfand

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Hemangiosarcoma, a natural model of human angiosarcoma, is an aggressive vascular tumor diagnosed commonly in dogs. The documented expression of several receptor tyrosine kinases (RTKs) by these tumors makes them attractive targets for therapeutic intervention using tyrosine kinase inhibitors (TKIs). However, we possess limited knowledge of the effects of TKIs on hemangiosarcoma as well as other soft tissue sarcomas. We report here on the use of the TKIs imatinib and dasatinib in canine hemangiosarcoma and their effects on platelet-derived growth factor receptor β (PDGFR-β) and Src inhibition. Both TKIs reduced cell viability, but dasatinib was markedly more potent in this regard, mediating cytotoxic effects orders of magnitude greater than imatinib. Dasatinib also inhibited the phosphorylation of the shared PDGFR-β target at a concentration approximately 1000 times less than that needed by imatinib and effectively blocked Src phosphorylation. Both inhibitors augmented the response to doxorubicin, suggesting that clinical responses likely will be improved using both drugs in combination; however, dasatinib was significantly (P <.05) more effective in this context. Despite the higher concentrations needed in cell-based assays, imatinib significantly inhibited tumor growth (P <.05) in a tumor xenograft model, highlighting that disruption of PDGFR-β/PDGF signaling may be important in targeting the angiogenic nature of these tumors. Treatment of a dog with spontaneously occurring hemangiosarcoma established that clinically achievable doses of dasatinib may be realized in dogs and provides a means to investigate the effect of TKIs on soft tissue sarcomas in a large animal model.

Original languageEnglish (US)
Pages (from-to)158-168
Number of pages11
JournalTranslational Oncology
Volume6
Issue number2
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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