Targeting the Interaction of G Beta-Gamma and Mutant G Alpha q/11 in Uveal Melanoma
Abstract
This Idea Award project addresses inhibition of mutant forms of GNAQ and GNA11, early drivers of oncogenesis in more than 90% of uveal melanomas, rare melanomas that occur in the eye and frequently metastasize to the liver. This project is responsive to the MRP Idea Award announcement that “encourages studies for rare melanomas across the entire spectrum from initiation to distant macrometastasis.” Moreover, this project addresses the Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Area of Therapeutic Prevention, and this project also addresses the FY20 MRP Challenge Statement by focusing on mutant GNAQ and GNA11, which cause alterations of signaling pathways in uveal melanoma. GNAQ and GNA11 are genes coding for highly similar proteins termed G protein alpha q and alpha 11. These G proteins are important regulators of cellular pathways that regulate the proliferation of melanocytes. Their activity is normally tightly controlled by switching between an inactive GDP-bound state and an active GTP-bound state. However, in uveal melanoma GNAQ or GNA11 is frequently mutated at the amino acid glutamine 209 (Q209) with the result that mutant GNAQ or GNA11 is locked in the active GTP-bound state, thus driving uncontrolled cell proliferation. Normally, G protein alpha subunits in the GDP-bound inactive state bind to G protein beta-gamma subunits, but are released from their partner G protein beta-gamma subunits upon becoming active by binding GTP. Thus, activated mutants of alpha q and alpha 11 that are found as drivers of uveal melanoma are thought to function independently of G protein beta-gamma subunits. However, our work and this Idea Award proposal show surprisingly that mutant alpha q and alpha 11 require interaction with G protein beta-gamma subunits to function. One major objective of this proposal is to challenge the existing paradigm of the requirement for G protein beta-gamma subunits by showing that disruption of the interaction of mutant alpha q or alpha 11 with beta-gamma is a potential therapeutic target in uveal melanoma. A second aspect of this project is our novel finding of differing sensitivity to inhibition of the two major alpha q and alpha 11 cancer-causing mutations, termed Q209L and Q209P. Our biochemical and cell-based studies show that oncogenic signaling by Q209P mutants of alpha q or alpha 11 is much more sensitive to inhibition by disruption of beta-gamma interaction than is oncogenic signaling by Q209L. Moreover, a retrospective clinical analysis by our team has uncovered for the first time, a difference in survival for metastatic uveal melanoma patients depending upon the presence of the Q209P versus the Q209L mutation. Thus, this proposal is also exploring this novel idea with the long-term implication that uveal melanoma patients with different mutations in alpha q or alpha 11 may have different outcomes and therapeutic treatments. Currently, there are no effective therapies for metastatic uveal melanoma, and a major goal in the field is to develop novel ways to inhibit mutant alpha q and alpha 11. Ultimately it is anticipated that this project will reveal the alpha q/11 interaction with beta-gamma as a novel target and thereby contribute to the development of drugs to block the overactive function of mutant alpha q and alpha 11.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110727
Entities
People
- Philip Wedegaertner
Organizations
- Thomas Jefferson University
- United States Army