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

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

doi:10.1016/j.ygyno.2014.04.044

Cited by 51 publications

(36 citation statements)

References 36 publications

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“…However, despite an initial objective response rate of approximately 60%, many patients succumb to their disease due to chemoresistance and tumor relapse (7,20). Recently, several FAK inhibitors were shown to suppress ovarian cancer progression by resensitizing cells to routine chemotherapies (21)(22)(23). Because NISCH is an upstream regulator of FAK, we thus, evaluated NISCH expression as a biomarker for potential sensitivity to FAK inhibition.…”

Section: Discussionmentioning

confidence: 99%

Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

Dong

et al. 2015

Molecular Cancer Therapeutics

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NISCH encodes the imidazoline receptor Nischarin and is a known tumor suppressor in many human malignancies; however, its roles in ovarian cancer are still largely unknown. Here, we aim to investigate the biologic functions of NISCH in ovarian cancer. We found that NISCH was significantly downregulated, which correlated considerably with advanced tumor stage, poor differentiation, lymph node metastasis, and the serous/mucinous subtypes in a panel of ovarian cancer tissues. Moreover, NISCH gene silencing was mainly the product of promoter hypermethylation, which could be reversed by treatment with 5-aza-dC. In vitro, NISCH overexpression suppressed cell proliferation and colony formation by hindering cell-cycle progression, whereas the opposite was observed in NISCH knockdown counterparts. In vivo, abundant NISCH expression hindered the growth of HO8910 xenografts, whereas NISCH knockdown accelerated the growth of SKOV3 xenografts. In addition, NISCH significantly attenuated cell invasion by inhibiting the phosphorylation of FAK and ERK, which could be neutralized by PF-562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knockdown xenografts exhibited increased peritoneal/pelvic metastases that were not present in counterparts treated with PF-562271. Furthermore, NISCH expression in primary ovarian cancer cells predicted a cellular resistance to PF-562271. In conclusion, we showed that NISCH was frequently silenced by promoter hypermethylation in human ovarian cancer. NISCH manipulated cellular proliferation and invasion by arresting cell cycle and inhibiting the FAK signal. Our findings revealed the biologic functions of NISCH in ovarian cancer, and might be useful for treating patients with aberrant expression of NISCH.

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Section: Discussionmentioning

confidence: 99%

Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

Dong

et al. 2015

Molecular Cancer Therapeutics

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“…Particularly in mesothelioma cells with inactivating mutations in the NF2 gene, which encodes the Merlin tumor suppressor protein, survival and proliferation signals are mediated through cell-ECM rather than cadherin cell-cell contact signals 125 . Low Merlin protein levels are therefore predicted to serve as a biomarker for FAK inhibitor sensitivity in mesothelioma (Trial ID: NCT01870609) and possibly also in ovarian cancer 126 .…”

Section: Fak In Clinical Applicationsmentioning

confidence: 99%

“…Lastly, FAK inhibitors may possess single agent activity in cancers where FAK expression and activity are amplified or where tumor cells become dependent on FAK-associated signals 126, 134, 135 . Examples include Ewing sarcoma 134 or ovarian serous carcinoma 135 , where treatment with the FAK inhibitor PF-562,271 blocked in vitro and in vivo tumor growth in pre-clinical studies.…”

Section: Fak’s Future As a Therapeutic Targetmentioning

confidence: 99%

FAK in cancer: mechanistic findings and clinical applications

2014

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Preface Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is over-expressed and activated in several advanced-stage solid cancers. FAK promotes tumor progression and metastasis through effects on cancer cells, as well as stromal cells of the tumor microenvironment. FAK’s kinase-dependent and –independent functions control cell movement, invasion, survival, gene expression, and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumor growth and metastasis in several preclinical models and possess initial clinical activity in patients with limited adverse events. We discuss FAK signaling effects on both tumor and stromal cell biology that provide rationale and support for future therapeutic opportunities.

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“…Additional factors including stromal contributions are also likely to influence the link between pFAK [Y397] inhibition and slowing of tumor growth and metastasis. The FAK/PYK2 inhibitor PF-562,271 is reported to reduce pFAK [Y397] without slowing growth of several ovarian tumor cells, including SKOV3, OVCAR10, and IGROV1-IP cells in vitro and 5009-MOVCAR cells in mice [37]. Despite this feature, PF-562,271 decreases metastatic spread of these tumors [37], as it does in an ovarian cancer model (ID8-IP) where tumor size and pFAK [Y397] are reduced [17].…”

Section: Discussionmentioning

confidence: 99%

Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors

Moen

Gebre

Alonso-Camino

et al. 2015

Clin Exp Metastasis

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The present study sought to determine the anti-tumor effects of OXA-11, a potent, novel small-molecule amino pyrimidine inhibitor (1.2 pM biochemical IC50) of focal adhesion kinase (FAK). In studies of cancer cell lines, OXA-11 inhibited FAK phosphorylation at phospho-tyrosine 397 with a mechanistic IC50 of 1 nM in TOV21G tumor cells, which translated into functional suppression of proliferation in 3-dimensional culture with an EC50 of 9 nM. Studies of OXA-11 activity in TOV21G tumor-cell xenografts in mice revealed a pharmacodynamic EC50 of 1.8 nM, indicative of mechanistic inhibition of pFAK [Y397] in these tumors. OXA-11 inhibited TOV21G tumor growth in a dose-dependent manner and also potentiated effects of cisplatin on tumor cell proliferation and apoptosis in vitro and on tumor growth in mice. Studies of pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice revealed OXA-11 suppression of pFAK [Y397] and pFAK [Y861] in tumors and liver. OXA-11 given daily from age 14 to 17 weeks reduced tumor vascularity, invasion, and when given together with the anti-VEGFR-2 antibody DC101 reduced the incidence, abundance, and size of liver metastases. Liver micrometastases were found in 100 % of mice treated with vehicle, 84 % of mice treated with OXA-11, and 79 % of mice treated with DC101 (19–24 mice per group). In contrast, liver micrometastases were found in only 52 % of 21 mice treated with OXA-11 plus DC101, and those present were significantly smaller and less numerous. Together, these findings indicate that OXA-11 is a potent and selective inhibitor of FAK phosphorylation in vitro and in vivo. OXA-11 slows tumor growth, potentiates the anti-tumor actions of cisplatin and—when combined with VEGFR-2 blockade—reduces metastasis of pancreatic neuroendocrine tumors in RIP-Tag2 mice.

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

Cited by 51 publications

References 36 publications

Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway

FAK in cancer: mechanistic findings and clinical applications

Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors

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