High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

Summary

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the “ dark kinome.” We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

Graphical abstract

Highlights

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  A chemogenetic drug screen in uveal melanoma reveals darovasertib as a top hit

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  Darovasertib is a dual inhibitor of PKC and PRK/PKN

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  Downstream of mutant Gαq, darovasertib blocks ERK and diminishes FAK activity

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  Darovasertib + FAKi act synergistically in preclinical uveal melanoma models

Abstract

Arang et al. define the druggable landscape of uveal melanoma and identify darovasertib as the top hit. Darovsertib acts as a dual PKC and PRK/PKN inhibitor, thereby blocking ERK and diminishing FAK activity. Darovasertib combined with FAK inhibition is highly synergistic in preclinical models of primary and metastatic uveal melanoma.