FAK Is a Critical Mediator of GNAQ-Driven Uveal Melanoma

Uveal melanoma (UM) is characterized by gain-of-function mutations in GNAQ or GNA11, which encode Gαq G proteins. However, the molecular mechanisms underlying Gαq-mediated cancer cell growth remain unknown, and there are currently no effective therapies for UM. Feng, Arang, and colleagues utilized an integrated bioinformatics pipeline to identify PTK2, which encodes focal adhesion kinase (FAK), as a clinically actionable synthetic lethal gene target in GNAQ-activated UM. Although PTK2 is not mutated in UM, expression of PTK2 inversely correlated with overall patient survival. Overexpression of an active Gαq mutant or activation of an inducible Gαq in UM cells resulted in increased active phosphorylation of FAK; conversely, knockdown or inhibition of Gαq diminished FAK activation, indicating that FAK acts downstream of Gαq. This activation occurred via the noncanonical TRIO-dependent signaling pathway and resulted in RhoA activation and subsequent changes to the cytoskeletion and actomyosin-initiated cell signaling. Inhibition of FAK (FAKi) with either of two chemically distinct FAK inhibitors revealed a dose-dependent sensitivity to FAKi and abolished colony-forming capacity in UM in vitro. FAKi resulted in a significant reduction of nuclear accumulation of the YES-associated protein (YAP) transcription factor and downregulation of YAP target genes. Similarly, knockdown or inhibition of Gαq or FAK reduced active YAP phosphorylation and increased repressive YAP phosphorylation, suggesting that the cellular effects of FAKi in UM are mediated by reduced YAP activity. Phosphorylation of MOB kinase activator 1A (MOB1A) by FAK resulted in dissociation of YAP from the Hippo repressor complex and increased YAP transcriptional activity. In vivo, treatment with FAK inhibitors reduced UM tumor size and cell proliferation and increased cytoplasmic retention of YAP. Taken together, these results indicate that pharmacologic inhibition of FAK deactivates oncogenic signaling pathways and may be a viable therapeutic strategy in patients with UM.

Feng X, Arang N, Rigiracciolo DC, Lee JS, Yeerna H, Wang Z, et al. A platform of synthetic lethal gene interaction networks reveals that the GNAQ uveal melanoma oncogene controls the Hippo pathway through FAK. Cancer Cell 2019 Feb 14 [Epub ahead of print].

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