Cross-talk between EphA2 and BRaf/CRaf is a key determinant of response to dasatinib

Jie Huang, Wei Hu, Justin Bottsford-Miller, Tao Liu, Hee Dong Han, Behrouz Zand, Sunila Pradeep, Ju Won Roh, Duangmani Thanapprapasr, Heather J. Dalton, Chad V. Pecot, Rajesh Rupaimoole, Chunhua Lu, Bryan Fellman, Diana Urbauer, Yu Kang, Nicholas B. Jennings, Li Huang, Michael T. Deavers, Russell BroaddusRobert L. Coleman, Anil K. Sood

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Purpose: EphA2 is an attractive therapeutic target because of its diverse roles in cancer growth and progression. Dasatinib is a multikinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed. Experimental design: The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot analysis, and plasmid transfection. In vivo , an orthotopic mouse model of uterine cancer was utilized to identify the biologic effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using reverse phase protein array (RPPA), immunoprecipitation, and double immunofluorescence staining. Results: We show that high levels of CAV-1, EphA2 phosphorylation at S897, and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRafS338, pMAPKT202/Y204 (mitogen-activated protein kinase [MAPK] pathway), pS6S240/244, p70S6kT389 (mTOR pathway), and pAKTS473. A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment. Conclusions: Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinibbased clinical trials.

Original languageEnglish (US)
Pages (from-to)1846-1855
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number7
DOIs
StatePublished - Apr 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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