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

Autor:	Arang N; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA., Lubrano S; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacy, University of Pisa, Pisa, Italy., Ceribelli M; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Rigiracciolo DC; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA., Saddawi-Konefka R; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA., Faraji F; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA., Ramirez SI; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA., Kim D; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA., Tosto FA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Stevenson E; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA., Zhou Y; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA., Wang Z; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA., Bogomolovas J; School of Medicine, University of California San Diego, La Jolla, CA 92093, USA., Molinolo AA; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA., Swaney DL; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA., Krogan NJ; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA., Yang J; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA., Coma S; Verastem Oncology, Needham, MA 02494, USA., Pachter JA; Verastem Oncology, Needham, MA 02494, USA., Aplin AE; Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA., Alessi DR; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Thomas CJ; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Gutkind JS; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: sgutkind@health.ucsd.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Nov 21; Vol. 4 (11), pp. 101244. Date of Electronic Publication: 2023 Oct 18.
DOI:	10.1016/j.xcrm.2023.101244
Abstrakt:	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. Competing Interests: Declaration of interests J.S.G. reports consulting fees from Domain Pharmaceuticals, Pangea Therapeutics, and io9 and is founder of Kadima Pharmaceuticals, all unrelated to the current study. J.S.G. and N.A. hold patent US11679113B2 related in part to this work. The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. N.J.K. has financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Maze Therapeutics, Interline Therapeutics, Rezo Therapeutics, Gen1E Lifesciences, Inc., and Twist Bioscience Corp. He is on the Board of Directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics. D.L.S. has a consulting agreement with Maze Therapeutics. J.B. is a consultant for Rocket Pharma. J.A.P. and S.C. are employees of Verastem, which has not influenced this study. Other authors declare no competing financial interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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