title: PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer.
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.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Duangmani
authors.initials: D
authors.lastname: Thanapprapasr
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Previs
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Piotr L
authors.initials: PL
authors.lastname: Dorniak
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Hansen
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Rouba
authors.initials: R
authors.lastname: Ali-Fehmi
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008819:Mice, Nude; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014594:Uterine Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; C000600809:GSK2256098; D006877:Hydroxamic Acids; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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