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

Abstract

Purpose: 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 GNAQ/GNA11, 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. GNAQ promotes the activation of YAP1, a key oncogenic driver, through focal adhesion kinase (FAK), thereby identifying FAK as a druggable signaling hub downstream from GNAQ. However, targeted therapies often activate compensatory resistance mechanisms leading to cancer relapse and treatment failure. Experimental Design: 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 in vitro and in vivo experimental systems. Results: 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 in vivo. Conclusions: 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. See related commentary by Harbour, p. 2967

Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy

“…MEK inhibitors when combined with dacarbazine or other chemotherapy agents failed to improve progression free survival in UM ( 226 ). However, new combination treatments co-targeting MEK with PKC, FAK, GNAQ/11 and other main pathways such as YAP have revealed promising new therapeutic vulnerabilities that can be exploited in a clinical manner (NCT03875820) ( 227 – 229 ). Remarkably, a state-of-the-art immunotherapy agent, Tebentafusp, is showing clinical benefit in patients with advanced UM.…”

CRISPR screening identifies CDK12 as a conservative vulnerability of prostate cancer

“…Current genome-scale CRISPR/Cas9 screens have been successfully used to identify genes required for cancer cell survival as candidate targets [ 9 , 10 ], while their further synergy with existing medicine has been less studied. Relatively, studies used CRISPR/Cas9 screens and focused on specific genes of “synthetic lethality” for clinical drugs, but neglected cancer dependencies under medicated stress [ 11 , 12 ]. This screening strategy provides potential targets for synergy, while attenuates the applicable value for monotherapy to a certain extent.…”

Targeting GPCRs & their Signaling as a Therapeutic Option in Melanoma

“…(ii) the direct activation of YAP1 by releasing this angiomotin transcription factor (AMOT) [207,210]. In uveal melanoma, the activation of Rho and Rac is linked to the activation of the MAP kinases JNK & p38 [209].…”