ArticleCell reports. Medicine2023
High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma.
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Article in Cell reports. Medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21citing papers in PubMed
5.9field-weighted citation impact, top 3% of its field
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Who cites it
21 citing papers in PubMed, 23 citations in OpenAlex.
- Oncogenic Gα signaling requires AP-3-dependent recruitment to the endolysosomal compartment.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A Phase II Trial of Defactinib Combined with Avutometinib in Patients with Metastatic Uveal Melanoma.Cancers · 2026Article
- Decellularized Dermis ECM-Based Melanoma-on-a-Chip Model with Integrated Lymphatic and Vascular Networks for High-Throughput Drug Testing.ACS applied bio materials · 2026Article
- Eukaryote initiation factor 6 modulates small-cell lung carcinoma plasticity via the integrin-FAK signaling axis.Nature communications · 2026Article
- RhoE downregulation leads to enhanced cholesterol biosynthesis and sorafenib resistance in hepatocellular carcinoma.The Journal of biological chemistry · 2025Article
- Functions and clinical implications of the liver microenvironment in hepatic uveal melanoma metastases.Cancer metastasis reviews · 2025Review
- KLK5 and KLK7 drive cervical carcinoma via KLK14-dependent RhoA and NF-κB pathways.Translational oncology · 2025Article
- Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma.The Journal of biological chemistry · 2025Article
- Multiple Epigenetic Mechanisms Functionally Cooperate to Silence Expression of Somatostatin Receptor Type 2 in Pancreatic Neuroendocrine Tumors.bioRxiv : the preprint server for biology · 2025Article
- Focal adhesion kinase/Src family kinase axis-mediated tyrosine phosphorylation of metabolic enzymes facilitates tumor metastasis.Signal transduction and targeted therapy · 2025Article
- A Brief Overview of Uveal Melanoma Treatment Methods with a Focus on the Latest Advances.Journal of clinical medicine · 2025Article
- Current Therapies and Potential Strategies for Uveal Melanoma.Drugs and drug candidates · 2025Article
- The guanine nucleotide exchange factor Ric-8A regulates the sensitivity of constitutively active Gαq to the inhibitor YM-254890.The Journal of biological chemistry · 2025Article
- PKN2 Is a Dependency of the Mesenchymal-like Cancer Cell State.Cancer discovery · 2025Article
- Single-Cell Transcriptomic Reveals the Involvement of Cell-Cell Junctions in the Early Development of Hypertrophic Cardiomyopathy.Journal of cellular and molecular medicine · 2025Article
- Target fishing: from "needle in haystack" to "precise guidance"--new technology, new strategy and new opportunity.Frontiers in pharmacology · 2025Review
- Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated GMolecular pharmacology · 2024Review
- The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence.Science signaling · 2024Review
- Review
- Capillary malformations.The Journal of clinical investigation · 2024Review
Corrections and comments
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Authors and funding
23 authors at 7 institutions in 3 countries.
Nadia ArangMoores 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.
Simone LubranoMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Pharmacy, University of Pisa, Pisa, Italy.
Michele CeribelliDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Damiano C RigiraccioloMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Robert Saddawi-KonefkaMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Farhoud FarajiMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Sydney I RamirezMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Daehwan KimMoores 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.
Frances A TostoDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Erica StevensonQuantitative 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.
Yuan ZhouQuantitative 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.
Zhiyong WangMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Julius BogomolovasSchool of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Alfredo A MolinoloMoores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
Danielle L SwaneyQuantitative 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.
Nevan J KroganQuantitative 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.
Jing YangMoores 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.
Silvia ComaVerastem Oncology, Needham, MA 02494, USA.
Jonathan A PachterVerastem Oncology, Needham, MA 02494, USA.
Andrew E AplinDepartment of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Dario R AlessiMedical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Craig J ThomasDivision of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
J Silvio GutkindMoores 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.
University of California San Diego · USQB3 · USNational Institutes of Health · USVerastem (United States) · USThomas Jefferson University · USUniversity of Dundee · GBUniversity of Pisa · IT
Funding
The Cancer Cell Map Initiative v2.0U54CA274502 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Emma Lundberg · 2022 to 2026
$14.2MGRADUATE TRAINING IN CELLULAR &MOLECULAR PHARMACOLOGYT32GM007752 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BROWN, JOAN HELLER, HANDEL, TRACY M · 1985 to 2023
$13.5MUsing Networks to Seed Hierarchical Whole-cell Models of CancerU54CA209891 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI IDEKER, TREY · 2017 to 2021
$10.9MRegulation of Tumor Invasion and Metastasis by Matrix StiffnessR01CA174869 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Jing Yang · 2015 to 2026
$4.3MEPHA2 Receptor Signaling in Breast Cancer MechanotransductionR01CA262794 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI ELENA B PASQUALE, Jing Yang · 2022 to 2026
$2.9MTargeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal MelanomaR01CA257505 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI APLIN, ANDREW ERIC, GUTKIND, JORGE SILVIO · 2021 to 2025
$2.7MFunctional interplay between Hippo and estrogen receptor ESR1R01CA268179 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Jing Yang · 2022 to 2026
$2.1MOTOLARYNGOLOGY TRAINING IN IMMUN., VIROL. &MOLEC. BIOL.T32DC000028 · NIDCD · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI RYAN, ALLEN F. · 1989 to 2020
$2.1MApical-basal polarity in tumor progression and metastasisR01CA236386 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI YANG, JING · 2019 to 2023
$1.9MFACSAria II Cell SorterS10RR027366 · NCRR · LA JOLLA INSTITUTE FOR IMMUNOLOGY · PI CROFT, MICHAEL · 2011 to 2011
$514kNCI NIH HHS R01 CA174869NCI NIH HHS R01 CA236386NCI NIH HHS R01 CA257505NCI NIH HHS R01 CA262794NCI NIH HHS R01 CA268179NCI NIH HHS U54 CA209891NCI NIH HHS U54 CA274502NCRR NIH HHS S10 RR027366NIDCD NIH HHS T32 DC000028NIGMS NIH HHS T32 GM007752
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.
Indexed as
MelanomaSkin NeoplasmsUveal NeoplasmsAnimalsDrug Evaluation, PreclinicalGTP-Binding Protein alpha SubunitsGTP-Binding Protein alpha Subunits, Gq-G11MiceProtein Kinase InhibitorsUveal MelanomaGTP-Binding Protein alpha SubunitsGTP-Binding Protein alpha Subunits, Gq-G11Protein Kinase Inhibitorschemogenetic drug screeningcombination therapyFAKGNAQmelanomaPKCPKN/PRKprecision medicinesynthetic lethality
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Read underepoch 390
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.