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

Nadia Arang; Simone Lubrano; Michele Ceribelli; Damiano C Rigiracciolo; Robert Saddawi-Konefka; Farhoud Faraji; Sydney I Ramirez; Daehwan Kim; Frances A Tosto; Erica Stevenson; Yuan Zhou; Zhiyong Wang; Julius Bogomolovas; Alfredo A Molinolo; Danielle L Swaney; Nevan J Krogan; Jing Yang; Silvia Coma; Jonathan A Pachter; Andrew E Aplin; Dario R Alessi; Craig J Thomas; J Silvio Gutkind

doi:10.1016/j.xcrm.2023.101244

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

Cell Rep Med. 2023 Nov 21;4(11):101244. doi: 10.1016/j.xcrm.2023.101244. Epub 2023 Oct 18.

Authors

Nadia Arang¹, Simone Lubrano², Michele Ceribelli³, Damiano C Rigiracciolo⁴, Robert Saddawi-Konefka⁴, Farhoud Faraji⁴, Sydney I Ramirez⁴, Daehwan Kim⁵, Frances A Tosto³, Erica Stevenson⁶, Yuan Zhou⁶, Zhiyong Wang⁴, Julius Bogomolovas⁷, Alfredo A Molinolo⁴, Danielle L Swaney⁶, Nevan J Krogan⁶, Jing Yang⁸, Silvia Coma⁹, Jonathan A Pachter⁹, Andrew E Aplin¹⁰, Dario R Alessi¹¹, Craig J Thomas³, J Silvio Gutkind¹²

Affiliations

¹ 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.
² Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacy, University of Pisa, Pisa, Italy.
³ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
⁴ Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
⁵ 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.
⁶ 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.
⁷ School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁸ 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.
⁹ Verastem Oncology, Needham, MA 02494, USA.
¹⁰ Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
¹¹ Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
¹² 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.

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.

Keywords: FAK; GNAQ; PKC; PKN/PRK; chemogenetic drug screening; combination therapy; melanoma; precision medicine; synthetic lethality.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Drug Evaluation, Preclinical
GTP-Binding Protein alpha Subunits / genetics
GTP-Binding Protein alpha Subunits / metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
GTP-Binding Protein alpha Subunits, Gq-G11 / therapeutic use
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / pathology
Mice
Protein Kinase Inhibitors / pharmacology
Skin Neoplasms*
Uveal Neoplasms* / drug therapy
Uveal Neoplasms* / genetics
Uveal Neoplasms* / metabolism

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

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