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Targeting GNAQ/11 through PKC inhibition in uveal melanoma

Cancer Gene Therapy volume 29, pages 1809–1813 (2022)Cite this article

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Abstract

Uveal melanoma is a rare malignancy affecting 5.1 patients/million per year with definitive treatment options of enucleation or radiation therapy to the primary tumor. Unfortunately, no FDA-approved systemic therapies exist for patients in the adjuvant or metastatic setting. Molecular profiling over the past decade has helped define uveal melanomas by characteristic mutations: GNAQ, GNA11, BAP1, SF3B1, and EIF1AX mutations. GNAQ/11 mutations are present in over 90% of patients with uveal melanoma and lead to signal transduction through G-protein coupled receptors to downstream growth factors. PKC inhibition has been an active area of investigation targeting this pathway specific to uveal melanoma. Several molecules have been developed and evaluated in clinical trials. Responses have been noted but clinical development has also yielded multiple toxicities and pathways of resistance limiting both breadth and durability of responses leading to combination therapy approaches. PKC inhibition remains an active and encouraging area of research to determine effective therapies for patients with uveal melanoma.

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Fig. 1: Uveal melanoma tumor-initiating mutations.
Fig. 2: GNAQ/11 pathway activation.

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No financial assistance was received in support of the manuscript.

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Authors and Affiliations

  1. Sarah Cannon Research Institute, 1100 Dr. Martin Luther King Jr. Blvd., Suite 800, Nashville, TN, 37203, USA

    Caressa D. Lietman

  2. Sarah Cannon Research Institute, Tennessee Oncology, 250 25th Ave North, Suite 200, Nashville, TN, 37203, USA

    Meredith McKean

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Both authors acquired the content and interpreted it, as well as drafted/revised the manuscript, approved the final version, and agreed to be accountable for all aspects of the work.

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Correspondence to Meredith McKean.

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CL has no competing financial interest to disclose. MM has the following competing interests: Research Grants—Paid to Institution—Ascentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxikon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Bayer, BioMed Valley Discoveries, EMD Serono, MedImmune, Nektar Therapeutics, Pfizer, Teneobio, Arvinas, Tempest Therapeutics, Arcus Biosciences, Synthorax, Alpine Immune, Scholar Rock, BioNTech, Erasca, Kechow Pharma, Mereo BioPharma, Foghorn Therapeutics, Pyramid Biosciences, PACT pharma, ImmVira Pharma, Kinnate Biopharma, Metabomed. Consulting/Advisory Role—Paid to Institution—Array BioPharma, AstraZeneca, MedPage Today, Pfizer, Regeneron Pharmaceuticals, Astellas Pharma, BicycleTx Limited, Castle Biosciences, Ideaya Biosciences, iTeos.

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Lietman, C.D., McKean, M. Targeting GNAQ/11 through PKC inhibition in uveal melanoma. Cancer Gene Ther 29, 1809–1813 (2022). https://doi.org/10.1038/s41417-022-00437-6

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