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

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Abstract

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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Notes

  1. VS-6063/PF-04554878 (Verastem), GSK2256098 (GlaxoSmithKline), PF-00562271 (Pfizer), VS-4718 (Verastem), BI-853520 (Boehringer Ingelheim), CEP-37440 (Teva Pharmaceuticals).

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Acknowledgments

We gratefully acknowledge the important contributions by Elisabeth Buck, Andrew Crew, and Maryland Franklin in performing the experiments with OXA-11 at OSI Pharmaceuticals. We also thank OSI for supplying OXA-11 for the studies performed at UCSF. The authors thank Maximilian Nitschké and Barbara Sennino for critical review of the manuscript and Brian Schriver for genotyping the RIP-Tag2 mice at UCSF. This work was supported in part by National Heart, Lung, and Blood Institute grants HL24136, HL59157, and HL127402 from the US National Institutes of Health (to DMcD), funding from OSI and AngelWorks Foundation (to DMcD), and an Overseas Research Fellowship from University of Bergen, Norway (to IM).

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  1. Ingrid Moen

    Present address: Oxy Solutions, Parkveien 33B, Oslo, Norway

  2. Matthew Gebre

    Present address: School of Medicine, Stony Brook University, Stony Brook, NY, USA

  3. Vanesa Alonso-Camino

    Present address: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

  4. Debbie Chen

    Present address: School of Medicine, University of California - Davis, Sacramento, CA, USA

Authors and Affiliations

  1. UCSF Helen Diller Family Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California - San Francisco, 513 Parnassus Avenue, Room S1349, San Francisco, CA, 94143-0452, USA

    Ingrid Moen, Matthew Gebre, Vanesa Alonso-Camino, Debbie Chen & Donald M. McDonald

  2. Department of Biomedicine, University of Bergen, Bergen, Norway

    Ingrid Moen

  3. Cancer & Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore

    David Epstein

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Moen, I., Gebre, M., Alonso-Camino, V. et al. Anti-metastatic action of FAK inhibitor OXA-11 in combination with VEGFR-2 signaling blockade in pancreatic neuroendocrine tumors. Clin Exp Metastasis 32, 799–817 (2015). https://doi.org/10.1007/s10585-015-9752-z

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