Disrupting the scaffold, an alternative approach to inhibiting FAK.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase. Consistent with its important roles in regulation of cell survival, migration and proliferation, FAK has been found to be up-regulated in a broad range of tumors. A large number of reports have shown that FAK is involved in cancer cell invasion, survival, metastasis, epithelial-to-mesenchymal transition (EMT), and maintenance of cancer stem cells. Additionally, FAK is important for vascular development and tumor angiogenesis. A recent study using an endothelial cell (EC)-specific tamoxifen-inducible FAK knockout mouse model has shown that endothelial FAK deletion in adult mice inhibits tumor growth and reduces tumor angiogenesis.1 Thus far, FAK has been considered an important drug target for cancer therapeutics. Several FAK inhibitors targeting FAK kinase activity have been developed, some of which have already been studied in clinical trials.Figure 1 Figure 1. The FAK scaffold inhibitor C4 inhibits melanoma growth by targeting both melanoma cells and endothelial cells. Recently, several studies have provided evidence that FAK can also regulate tumor growth in a kinase-independent manner through its scaffolding function. In one study, the disruption of FAK interaction with endophilin A2 through mutation of its Pro-878/881 motif suppressed mammary tumor growth and metastasis in a murine breast cancer model.2 In another example, Luo et al found that treatment with FAK inhibitor could only suppress the proliferation of luminal progenitor-like or basal subtype mammary tumor cells, but not MaSC-like or claudin-low subtype cells3. Moreover, expression of kinase-defective FAK was shown to rescue EC apoptosis resulting from FAK deletion in embryos, indicating that FAK scaffolding function is also important for EC survival.4 These data suggest that only targeting FAK kinase activity might not effectively block FAK involved pro-tumor signaling. Instead, targeting FAK scaffold function might be another promising approach. Several small molecules specifically targeting FAK scaffold function have been discovered by Cance's group, despite a big challenge in developing small molecules capable of disrupting protein-protein interactions.5,6 These inhibitors have shown significant anti-tumor activity in various human tumor cells, and poteintial for sensitizing tumors to chemotherapy. In a recent paper in Cell Cycle, Kurenova et al. investigated the activity of the FAK scaffold inhibitor C4, which targets the FAK/VEGFR3 complex, against melanoma.7 They found that C4 reduced phosphorylation of FAK and VEGFR3, decreasing complex formation. Importantly, C4 significantly reduced tumor growth in vivo and sensitized tumors to chemotherapy in both BRAF wild type and mutant melanomas. Interestingly, they showed that the anti-cancer activity of C4 was due to targeting of both melanoma cells and ECs. C4 inhibited FAK/VEGFR3 signaling in ECs and prevented vessel formation and sprouting. A significant reduction of tumor blood volume was seen following C4 treatment in a xenograft mouse model. This study by the Cance group further strengthens the evidence that blocking FAK-VEGFR3 scaffold signaling is highly effective in treating melanoma. More importantly, their data indicate that C4 may be a promising drug for treating patients harboring wild type BRAF, as prognoses are still very poor for these patients. This study also demonstrates the great therapeutical potential of targeting FAK scaffolding function. FAK interacts with different proteins, promising that future work in designing FAK scaffold inhibitors will contribute to the development of more effective cancer therapies.