Abstract 2823: Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition

Abstract

Abstract Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that undergoes gene amplification in >20% of serous ovarian cancers. In addition to increased tumor growth and spread, ovarian cancer patients with FAK amplification have a poorer prognosis with decreased overall survival. Merlin, a product of the NF2 tumor suppressor gene, is being evaluated as a biomarker for sensitivity to FAK inhibition in human clinical trials for malignant mesothelioma. As it remains undetermined whether linkages exist between merlin and FAK in other tumor types, we evaluated nine human and two murine ovarian cancer cell lines with sub-micromolar levels of FAK inhibitor (PF-271) for effects on anchorage-independent cell growth. Cells were identified as sensitive (OVCAR3, OVCAR8, HEY, ID8-IP), intermediate (A2780, IGROV1), or resistant (OVCAR10, IGROV1-IP, SKOV3, SKOV3-IP, 5009) to FAK inhibition. Notably, merlin protein levels were high in all resistant cell lines, moderate in intermediate cell lines, and low or undetectable in sensitive cell lines. Oral FAK inhibitor administration reduced orthotopic tumor growth of sensitive (ID8-IP, low merlin) but not resistant (5009, high merlin) murine ovarian carcinoma cells. However, stable knockdown of merlin expression in resistant SKOV3-IP and OVCAR10 human ovarian carcinoma cells did not induce sensitivity to FAK inhibition in vitro. These results support the notion that high merlin expression is correlated with a FAK-inhibitor resistant phenotype, likely through an indirect mechanistic linkage. Nevertheless, merlin protein levels may serve as a biomarker to predict ovarian cancer sensitivity or resistance to FAK inhibitor treatment. Supported by NIH CA102310 Citation Format: Nina R. Shah, Isabelle Tancioni, Kristy K. Ward, Christine Lawson, Xiao Lei Chen, Nichol L.G. Miller, Florian J. Sulzmaier, Sean Uryu, David D. Schlaepfer. Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2823. doi:10.1158/1538-7445.AM2014-2823