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Title: PTEN expression as a predictor of response to focal adhesion kinase inhibition in uterine cancer
Authors: Duangmani Thanapprapasr
Rebecca A. Previs
Wei Hu
Cristina Ivan
Guillermo N. Armaiz-Pena
Piotr L. Dorniak
Jean M. Hansen
Rajesha Rupaimoole
Jie Huang
Heather J. Dalton
Rouba Ali-Fehmi
Robert L. Coleman
Anil K. Sood
University of Texas MD Anderson Cancer Center
Mahidol University
Wayne State University
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Jun-2015
Citation: Molecular Cancer Therapeutics. Vol.14, No.6 (2015), 1466-1475
Abstract: © 2015 American Association for Cancer Research. PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wildtype models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAK<sup>Y397</sup> in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAK<sup>Y397</sup> expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAK<sup>Y397</sup> expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAK<sup>Y397</sup> expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development.
ISSN: 15388514
Appears in Collections:Scopus 2011-2015

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