Exploiting Protein Structural Dynamics for New Uveal Melanoma Therapies

ASPIRE Award (2023-Present)

Aashish Manglik, MD, PhD; Michelle Arkin, PhD; Boris Bastian, MD, PhD, University of California, San Francisco

Aashish Manglik, MD, PhD

Michelle Arkin, PhD

Boris Bastian, MD, PhD

Uveal melanoma (UM) is a devastating cancer that remains difficult to treat, with a 10-year mortality rate of 50%. Despite the successes of immune checkpoint blockade and targeted therapies in treating other types of melanoma, those therapies have been largely ineffective in treating uveal melanoma, so new therapeutic options and mechanistic understanding are desperately needed for this cancer subtype. Previously, Aashish Manglik and his collaborators identified the Gαq signaling pathway as the main driver of UM, with ~90% of cases harboring somatic mutations in one of the two Gαq/11 subunits, GNAQ or GNA11. The Gαq/11 subunits are GTPases which are coupled to G-protein coupled receptors, and act as switches to activate a variety of downstream effectors that control diverse signaling networks. The predominant GNAQ/11 mutations in UM lead to constitutive activation of the Gαq protein, leading to hyperactivation of the MAP-kinase pathway which drives cellular proliferation. Unfortunately, drugs targeting MAP-kinase pathway effectors such as MEK have had limited clinical efficacy in UM. And while there are compounds which inhibit the Gαq/11 subunits, their clinical utility is limited by cardiovascular and hemostatic toxicities due to equal inhibition of both wild-type and oncogenic Gαq/11.

Therefore, in this study, the investigators aim to develop targeted therapies that specifically inhibit mutant Gαq/11 oncoproteins over their WT counterparts, and continue to unravel the mechanism behind the oncogenic mutations. Preliminary biophysical studies from the team provide support for a distinct conformation of oncogenic Gαq/11 mutants. These observations open the door to discovery of a “wild type sparing” inhibitor which selectively targets only the oncogenic Gαq/11 proteins, thereby providing an effective therapeutic target for this central node in UM oncogenic signaling. Now this research team will perform cellular, biophysical, and structural studies to validate this new strategy which may lead to the discovery of new precision medicine therapies for uveal melanoma.