Whole genome CRISPR screening identifies PI3K/AKT as a downstream component of the oncogenic GNAQ-FAK signaling circuitry

G proteins and G proteins coupled receptors (GPCRs) activate a diverse array of signal transduction pathways that converge on the promotion of cell growth and survival. Indeed, hotspot activating mutations in GNAQ/GNA11, encoding Gq proteins, are driver oncogenes in uveal melanoma (UM) for which there are limited effective therapies currently available. Focal Adhesion Kinase (FAK) has been recently shown to be a central mediator of Gq-driven signaling in UM, and as a result, is being explored clinically as a therapeutic target for UM, alone or in combination therapies. Despite this, the repertoire of Gq/FAK regulated signaling mechanisms have not been fully elucidated. We used a whole-genome CRISPR screen in GNAQ-mutant UM cells to identify mechanisms that when overactivated lead to reduced sensitivity to FAK inhibition and found the PI3K/AKT signaling pathway to represent a major resistance driver.