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

Publication ,  Journal Article
Thanapprapasr, D; Previs, RA; Hu, W; Ivan, C; Armaiz-Pena, GN; Dorniak, PL; Hansen, JM; Rupaimoole, R; Huang, J; Dalton, HJ; Ali-Fehmi, R ...
Published in: Mol Cancer Ther
June 2015

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.

Duke Scholars

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

June 2015

Volume

14

Issue

6

Start / End Page

1466 / 1475

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Uterine Neoplasms
  • Proto-Oncogene Proteins c-akt
  • Prognosis
  • Predictive Value of Tests
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Phosphorylation
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Thanapprapasr, D., Previs, R. A., Hu, W., Ivan, C., Armaiz-Pena, G. N., Dorniak, P. L., … Sood, A. K. (2015). PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther, 14(6), 1466–1475. https://doi.org/10.1158/1535-7163.MCT-14-1077
Thanapprapasr, Duangmani, Rebecca A. Previs, Wei Hu, Cristina Ivan, Guillermo N. Armaiz-Pena, Piotr L. Dorniak, Jean M. Hansen, et al. “PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer.Mol Cancer Ther 14, no. 6 (June 2015): 1466–75. https://doi.org/10.1158/1535-7163.MCT-14-1077.
Thanapprapasr D, Previs RA, Hu W, Ivan C, Armaiz-Pena GN, Dorniak PL, et al. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther. 2015 Jun;14(6):1466–75.
Thanapprapasr, Duangmani, et al. “PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer.Mol Cancer Ther, vol. 14, no. 6, June 2015, pp. 1466–75. Pubmed, doi:10.1158/1535-7163.MCT-14-1077.
Thanapprapasr D, Previs RA, Hu W, Ivan C, Armaiz-Pena GN, Dorniak PL, Hansen JM, Rupaimoole R, Huang J, Dalton HJ, Ali-Fehmi R, Coleman RL, Sood AK. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. Mol Cancer Ther. 2015 Jun;14(6):1466–1475.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

June 2015

Volume

14

Issue

6

Start / End Page

1466 / 1475

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Uterine Neoplasms
  • Proto-Oncogene Proteins c-akt
  • Prognosis
  • Predictive Value of Tests
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Phosphorylation
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic