1. High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma
- Author
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Arang, Nadia, Lubrano, Simone, Ceribelli, Michele, Rigiracciolo, Damiano C, Saddawi-Konefka, Robert, Faraji, Farhoud, Ramirez, Sydney I, Kim, Daehwan, Tosto, Frances A, Stevenson, Erica, Zhou, Yuan, Wang, Zhiyong, Bogomolovas, Julius, Molinolo, Alfredo A, Swaney, Danielle L, Krogan, Nevan J, Yang, Jing, Coma, Silvia, Pachter, Jonathan A, Aplin, Andrew E, Alessi, Dario R, Thomas, Craig J, and Gutkind, J Silvio
- Subjects
Biomedical and Clinical Sciences ,Clinical Research ,Cancer ,Eye Disease and Disorders of Vision ,Rare Diseases ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Animals ,Mice ,Melanoma ,Skin Neoplasms ,GTP-Binding Protein alpha Subunits ,GTP-Binding Protein alpha Subunits ,Gq-G11 ,Drug Evaluation ,Preclinical ,Uveal Neoplasms ,Protein Kinase Inhibitors ,FAK ,GNAQ ,PKC ,PKN/PRK ,chemogenetic drug screening ,combination therapy ,melanoma ,precision medicine ,synthetic lethality ,Biomedical and clinical sciences - Abstract
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.
- Published
- 2023