TY - JOUR
T1 - PTEN expression as a predictor of response to focal adhesion kinase inhibition in uterine cancer
AU - Thanapprapasr, Duangmani
AU - Previs, Rebecca A.
AU - Hu, Wei
AU - Ivan, Cristina
AU - Armaiz-Pena, Guillermo N.
AU - Dorniak, Piotr L.
AU - Hansen, Jean M.
AU - Rupaimoole, Rajesha
AU - Huang, Jie
AU - Dalton, Heather J.
AU - Ali-Fehmi, Rouba
AU - Coleman, Robert L.
AU - Sood, Anil K.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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 pFAKY397 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 pFAKY397 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 pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 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.
AB - 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 pFAKY397 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 pFAKY397 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 pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 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.
UR - http://www.scopus.com/inward/record.url?scp=84942081974&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942081974&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-14-1077
DO - 10.1158/1535-7163.MCT-14-1077
M3 - Article
C2 - 25833835
AN - SCOPUS:84942081974
SN - 1535-7163
VL - 14
SP - 1466
EP - 1475
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 6
ER -