The GNAQ-oncogenic signaling network: Targeting FAK and its synthetic lethal interactome as a precision therapeutic approach against uveal melanoma
Hotspot activating mutations in GNAQ/GNA11, encoding Gαq proteins, are driver oncogenes in uveal melanoma (UM), the primary cancer of the eye in adults, with limited additional aberrancies. However, there are few effective therapies available for UM and metastatic UM (mUM) patients, posing a critical need for novel therapeutic strategies against UM and mUM. Here, we have focused our efforts on dissecting Gαq-regulated signaling circuitries towards a better understanding of how Gαq promotes aberrant cell growth when activated, and to identify which Gαq-regulated signaling events can serve as actionable therapeutic targets for the treatment of UM. Using the convergence of bioinformatic, genetic and biochemical investigation, we uncovered a molecular framework poising Focal Adhesion Kinase (FAK) as a central mediator of oncogenic Gαq-regulated signaling, and as a controller of YAP through a mechanism suppressing the Hippo kinase cascade. We show that FAK inhibitors (FAKi) suppress YAP activation in vivo and halt UM growth, exposing a signaling vulnerability that can be targeted for UM treatment. Further interrogation into Gαq/FAK-regulated signaling mechanisms demonstrates that in addition to YAP, FAK controls PI3K/AKT signaling, and that UM cells require PI3K/AKT signaling for survival. These findings establish a novel link between Gαq-driven signaling and the stimulation of PI3K, and the aberrant activation of signaling networks underlying the growth and survival of UM. Finally, through a high-throughput, chemogenetic drug screen we profile the druggable landscape of UM and identified PKC inhibitors (PKCi) as a class targeting UM-specific vulnerabilities. Of note, we identified one compound with the highest preferential activity against UM. We investigated the mechanism of action of this compound, revealing a unique activity profile inhibiting PKC and PKC-related kinases, priming it to target cell-essential pathways that drive tumor growth in UM. Further work demonstrated that the combination of PKCi and FAKi synergistically inhibit UM growth and promote cytotoxic cell death in vitro and in preclinical xenograft and metastatic mouse models representing an exciting and highly translatable therapeutic strategy against UM. Collectively, the data presented here provides a wealth of information that can be readily translated to fill the lack of precision therapies against UM.