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

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.

The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma

“…Since certain FAK inhibitors demonstrated a synergistic effect with cisplatin in other malignant diseases [9], cell viability was also measured when BI 853520 was applied in combination with cisplatin. In these experiments, we used the relatively sensitive and merlin-negative P31 and the more resistant and merlin-expressing SPC212 cells.…”

“…The promising results from trials using first-line bevacizumab, cisplatin, and pemetrexed combinations in MPM patients underline the importance of anti-angiogenic therapies in this particular malignancy [45]. Importantly, FAK as a downstream element integrates proangiogenic signals received both via VEGFRs and integrin receptors, and as such, it might further increase the efficacy of VEGFR-directed therapeutic modalities [9, 46]. For example, in vivo studies in pancreatic neuroendocrine tumors indicated reduced incidence and number and size of liver metastases following the combination of another FAK inhibitor (OXA-11) with VEGFR2 blockade [9].…”

“…Importantly, FAK as a downstream element integrates proangiogenic signals received both via VEGFRs and integrin receptors, and as such, it might further increase the efficacy of VEGFR-directed therapeutic modalities [9, 46]. For example, in vivo studies in pancreatic neuroendocrine tumors indicated reduced incidence and number and size of liver metastases following the combination of another FAK inhibitor (OXA-11) with VEGFR2 blockade [9]. Additionally, a recent study on ovarian cancer mouse models showed that combining anti-angiogenic agents with FAK inhibitors clearly reduces tumor growth and, moreover, that FAK inhibitor treatment following anti-angiogenic therapy withdrawal inhibits tumor rebound [46].…”

“…Accordingly, during homeostatic conditions, FAK activation mainly relies on signals from integrins and growth factor receptors, leading to autophosphorylation of the Y397 site in the N-terminal domain [3, 4, 6–8]. FAK overexpression has been preferentially linked to a more aggressive tumor behavior, particularly by promoting tumor cell proliferation, survival, motility, invasion, stem cell renewal, angiogenesis, and metastasis [4, 6, 7, 9–11]. In this context, there is emerging evidence for a functional role of FAK gene amplification and protein overexpression during tumor progression in different tumor types including lung, breast, colorectal, thyroid, kidney, and pancreatic cancers as well as astrocytoma and osteosarcoma [10, 12–14].…”

“…Recognition of the crucial role of FAK in the aforementioned tumor promoting functions prompted the development of FAK small molecule inhibitors and their application for cancer therapy [3, 6, 9, 14]. Early preclinical data provided a clear scientific rationale for the anti-tumorigenic effects mediated by FAK inhibitors, though concerns were raised about their potential toxicity via interacting with ATP binding sites on other tyrosine kinases [3].…”