Abstract 1921: A novel FAK kinase inhibitor (PF-4554878) decreases growth and induces apoptosis in pancreatic neuroendocrine tumor cells

Abstract

Abstract Introduction: Pancreatic neuroendocrine tumors (PNETs) are poorly understood and there are few effective therapies. Focal adhesion kinase (FAK) is an important tyrosine kinase implicated in cell survival signaling and found to be overexpressed in many malignancies. Our hypotheses are that 1) FAK expression is upregulated, 2) that FAK plays an important role in PNET cell survival, and 3) that a novel ATP competitive kinase inhibitor of FAK demonstrates anti-neoplastic efficacy in PNET cells. Methods: By Western blot, the expression of FAK was determined in frozen human PNETs compared to normal human pancreas. The compound, PF-4554878 (Pfizer), has been shown to be an ATP competitive kinase inhibitor of FAK. The in-vitro effects of this compound on cell signaling, viability and apoptosis in human pancreatic neuroendocrine cells (BON-1 and QGP-1) were evaluated. Statistical analysis was performed via t-test with significance defined as p<0.05. Results: FAK was found to be overexpressed in PNETs compared to normal pancreas. PF-4554878 not only caused a decrease in PNET cell viability with an IC50 of 5 µM in human pancreatic neuroendocrine cell lines, but also caused a statistically significant dose-dependent increase in apoptosis by TUNEL staining and/or PARP cleavage. These effects were associated with a decrease in Y397 phosphorylation of FAK. Conclusions: A novel compound that inhibits the kinase activity of FAK results in decreased PNET proliferation and induction of apoptosis. These effects appear to be mediated through downregulation of p-FAK (Y397). This compound deserves further study as a novel treatment strategy in human PNETs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1921. doi:1538-7445.AM2012-1921