Reference Detail

Ref Type

Journal Article

PMID

(25833835)

Authors

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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	6	2015 Jun	1466-1475	Mol Cancer Ther

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN wild-type	uterine cancer	decreased response	GSK2256098	Preclinical	Actionable	In a preclinical study, GSK2256098 treatment resulted in a decreased response in uterine cancer cells with PTEN wild-type versus uterine cancer cells harboring a PTEN mutation (PMID: 25833835).	25833835
PTEN mutant	uterine cancer	sensitive	GSK2256098	Preclinical	Actionable	In a preclinical study, uterine cancer cells harboring a PTEN mutation demonstrated sensitivity to GSK2256098, resulting in inhibition of Ptk2 (Fak) phosphorylation, decreased tumor growth, and apoptosis both in culture and in mouse models (PMID: 25833835).	25833835
PTEN mutant	uterine cancer	sensitive	GSK2256098 + Topotecan	Preclinical	Actionable	In a preclinical study, uterine cancer cells harboring a PTEN mutation were more sensitive to the combination of GSK2256098 and Hycamtin (topotecan) than uterine cancer cells wild-type for PTEN, resulting in decreased tumor growth in culture and in mouse models (PMID: 25833835).	25833835
PTEN mutant	uterine cancer	sensitive	GSK2256098 + Paclitaxel	Preclinical	Actionable	In a preclinical study, uterine cancer cells harboring a PTEN mutation were more sensitive to the combination of GSK2256098 and Taxol (paclitaxel) than uterine cancer cells wild-type for PTEN, resulting in decreased tumor growth in culture and in mouse models (PMID: 25833835).	25833835