Synthetic Lethal Screens Reveal Cotargeting FAK and MEK as a Multimodal Precision Therapy for GNAQ -Driven Uveal Melanoma

• Published in: Clinical cancer research Vol. 27; no. 11; pp. 3190 - 3200
• Main Authors: Paradis, Justine S, Acosta, Monica, Saddawi-Konefka, Robert, Kishore, Ayush, Gomes, Frederico, Arang, Nadia, Tiago, Manoela, Coma, Silvia, Lubrano, Simone, Wu, Xingyu, Ford, Kyle, Day, Chi-Ping, Merlino, Glenn, Mali, Prashant, Pachter, Jonathan A, Sato, Takami, Aplin, Andrew E, Gutkind, J Silvio
• Format: Journal Article
• Language: English
• Published: United States 01.06.2021
• Subjects: Animals; Combined Modality Therapy; Female; Focal Adhesion Kinase 1 - metabolism; Gain of Function Mutation; Genetic Testing - methods; GTP-Binding Protein alpha Subunits, Gq-G11 - genetics; HEK293 Cells; Humans; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; Melanoma - genetics; Melanoma - therapy; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Uveal Neoplasms - genetics; Uveal Neoplasms - therapy; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-20-3363

Uveal melanoma is the most common eye cancer in adults. Approximately 50% of patients with uveal melanoma develop metastatic uveal melanoma (mUM) in the liver, even after successful treatment of the primary lesions. mUM is refractory to current chemo- and immune-therapies, and most mUM patients die within a year. Uveal melanoma is characterized by gain-of-function mutations in / , encoding Gαq proteins. We have recently shown that the Gαq-oncogenic signaling circuitry involves a noncanonical pathway distinct from the classical activation of PLCβ and MEK-ERK. promotes the activation of YAP1, a key oncogenic driver, through focal adhesion kinase (FAK), thereby identifying FAK as a druggable signaling hub downstream from . However, targeted therapies often activate compensatory resistance mechanisms leading to cancer relapse and treatment failure. We performed a kinome-wide CRISPR-Cas9 sgRNA screen to identify synthetic lethal gene interactions that can be exploited therapeutically. Candidate adaptive resistance mechanisms were investigated by cotargeting strategies in uveal melanoma and mUM and experimental systems. sgRNAs targeting the PKC and MEK-ERK signaling pathways were significantly depleted after FAK inhibition, with ERK activation representing a predominant resistance mechanism. Pharmacologic inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in uveal melanoma cells and exerted cytotoxic effects, leading to tumor collapse in uveal melanoma xenograft and liver mUM models . Coupling the unique genetic landscape of uveal melanoma with the power of unbiased genetic screens, our studies reveal that FAK and MEK-ERK cotargeting may provide a new network-based precision therapeutic strategy for mUM treatment. .