1. Academic Validation
  2. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer

PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer

  • Mol Cancer Ther. 2015 Jun;14(6):1466-1475. doi: 10.1158/1535-7163.MCT-14-1077.
Duangmani Thanapprapasr  # 1 2 Rebecca A Previs  # 1 Wei Hu 1 Cristina Ivan 3 Guillermo N Armaiz-Pena 1 Piotr L Dorniak 1 Jean M Hansen 1 Rajesha Rupaimoole 1 Jie Huang 1 Heather J Dalton 1 Rouba Ali-Fehmi 4 Robert L Coleman 1 Anil K Sood 1 5 3
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
  • 3 Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 4 Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.
  • 5 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • # Contributed equally.
Abstract

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-wild-type models of uterine Cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAK(Y397) 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(Y397) 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(Y397) expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAK(Y397) 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.

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