Cross-talk between EphA2 and BRaf/CRaf is a key determinant of response to Dasatinib. Clin Cancer Res 2014 Apr 01;20(7):1846-55
Date
02/04/2014Pubmed ID
24486585Pubmed Central ID
PMC3975695DOI
10.1158/1078-0432.CCR-13-2141Scopus ID
2-s2.0-84898753092 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
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, pCRaf(S338), pMAPK(T202/Y204) (mitogen-activated protein kinase [MAPK] pathway), pS6(S240/244), p70S6k(T389) (mTOR pathway), and pAKT(S473). 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 dasatinib-based clinical trials.
Author List
Huang J, Hu W, Bottsford-Miller J, Liu T, Han HD, Zand B, Pradeep S, Roh JW, Thanapprapasr D, Dalton HJ, Pecot CV, Rupaimoole R, Lu C, Fellman B, Urbauer D, Kang Y, Jennings NB, Huang L, Deavers MT, Broaddus R, Coleman RL, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line, Tumor
Dasatinib
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Protein Kinase Inhibitors
Protein Multimerization
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf
Pyrimidines
Receptor, EphA2
Thiazoles
Uterine Neoplasms
