AbstractThe nonreceptor protein tyrosine kinase, focal adhesion kinase (FAK, also known as PTK2), is a key mediator of signal transduction downstream of integrins and growth factor receptors in a variety of cells, including endothelial cells. FAK is upregulated in several advanced-stage solid tumors and has been described to promote tumor progression and metastasis through effects on both tumor cells and stromal cells. This observation has led to the development of several FAK inhibitors, some of which have entered clinical trials (GSK2256098, VS-4718, VS-6062, VS-6063, and BI853520). Resistance to chemotherapy is a serious limitation of cancer treatment and, until recently, most studies were restricted to tumor cells, excluding the possible roles performed by the tumor microenvironment. A recent report identified endothelial cell FAK (EC-FAK) as a major regulator of chemosensitivity. By dysregulating endothelial cell–derived paracrine (also known as angiocrine) signals, loss of FAK solely in the endothelial cell compartment is able to induce chemosensitization to DNA-damaging therapies in the malignant cell compartment and thereby reduce tumor growth. Herein, we summarize the roles of EC-FAK in cancer and development and review the status of FAK-targeting anticancer strategies. Clin Cancer Res; 22(15); 3718–24. ©2016 AACR.

2014-07-01·Cancer Biology & Therapy3区 · 医学

Focal adhesion kinase

3区 · 医学

Article

作者: Kang, Yu ; DeGeest, Koen ; Akbani, Rehan ; Bottsford-Miller, Justin ; Lutgendorf, Susan ; Diao, Lixia ; Coleman, Robert L ; Sanguino, Angela M ; Nick, Alpa M ; Stone, Rebecca L ; Thanapprapasr, Duangmani ; Lopez-Berestein, Gabriel ; Zand, Behrouz ; Sood, Anil K ; Baggerly, Keith A ; Armaiz-Pena, Guillermo N ; Dalton, Heather J

This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.

2014-07-01·Gynecologic Oncology2区 · 医学

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer

2区 · 医学

Article

作者: Shah, Nina R ; Ward, Kristy K ; Tancioni, Isabelle ; Miller, Nichol L G ; Lawson, Christine ; Jean, Christine ; Uryu, Sean ; Sulzmaier, Florian J ; Schlaepfer, David D ; Chen, Xiao Lei ; Connolly, Denise C

OBJECTIVEFocal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined.METHODSNine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, also termed VS-6062) from 0.1 to 1 μM for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown.RESULTSGreater than 50% inhibition of OVCAR8, HEY, and ID8-IP ovarian carcinoma cell growth occurred with 0.1 μM PF-271 in anchorage-independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3-IP, A2780, and 5009-MOVCAR was not affected by 0.1 μM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition.CONCLUSIONSDifferential responsiveness to FAK inhibitor treatment was observed. Intrinsic low merlin protein level correlated with PF-271-mediated anchorage-independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials.

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