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Shah NR , Tancioni I , Ward KK , Lawson C , Chen XL , Jean C , Sulzmaier FJ , Uryu S , Miller NL , Connolly DC , Schlaepfer DD
Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer
Gynecol Oncol. 2014 Jul;134(1) :104-11
PMID: 24786638    PMCID: PMC4065804    URL: https://www.ncbi.nlm.nih.gov/pubmed/24786638
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OBJECTIVE: Focal 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. METHODS: Nine 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 muM 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. RESULTS: Greater than 50% inhibition of OVCAR8, HEY, and ID8-IP ovarian carcinoma cell growth occurred with 0.1 muM 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 muM 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. CONCLUSIONS: Differential 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.
Shah, Nina R Tancioni, Isabelle Ward, Kristy K Lawson, Christine Chen, Xiao Lei Jean, Christine Sulzmaier, Florian J Uryu, Sean Miller, Nichol L G Connolly, Denise C Schlaepfer, David D eng CA136596/CA/NCI NIH HHS/ T32 CA121938/CA/NCI NIH HHS/ CA151374/CA/NCI NIH HHS/ CA083638/CA/NCI NIH HHS/ R01 CA102310/CA/NCI NIH HHS/ CA006927/CA/NCI NIH HHS/ CA102310/CA/NCI NIH HHS/ R01 CA180769/CA/NCI NIH HHS/ P30 CA023100/CA/NCI NIH HHS/ CA158881/CA/NCI NIH HHS/ T32-CA121938/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Gynecol Oncol. 2014 Jul;134(1):104-11. doi: 10.1016/j.ygyno.2014.04.044. Epub 2014 Apr 27.