Saturday, May 4, 2024
5/4/2024
TITLE Biochemical properties and implications of NRAS mutant-specific BRAF interactions in melanoma ABSTRACT Extracellular growth factors promote cellular proliferation, motility, and survival through a complex network of signal transduction pathways. Thus, mutations in these pathways can cause inappropriate cellular proliferation and lead to diseases, such as cancer. RAS, an intracellular hub for multiple signaling pathways, is mutated in 20-30% of all human cancers. While the three RAS isoforms (H-, K-, and N-RAS) share a high degree of similarity, each RAS-driven cancer type is enriched for mutations in a specific RAS isoform, codon (12, 13, or 61), and amino acid. We do not fully understand the mechanism driving this observed selectivity, although each RAS mutant has distinct biochemical and functional properties. Elucidating the mechanisms underlying these mutational preferences could help identify the features of oncogenic RAS required to initiate cancer in different tissue types. To address this knowledge gap, we have focused on the selection of specific NRAS mutants in melanoma. Our work has shown that common melanoma-associated NRAS mutants (Q61R, K) promote MAPK signaling through increased activation of BRAF homo- and hetero-dimers. New molecular dynamics simulations suggest that conformational properties, specific to the NRAS mutants that drive melanoma, facilitate BRAF binding. Here, I will test the hypothesis that structural differences between NRAS mutants determine their ability to outcompete autoinhibitory BRAF interactions, drive enhanced MAPK>ERK activation, and alter the potency of RAF inhibitors. To test my hypothesis, I will use a variety of in vitro biosensors, cell-based signaling assays, and mouse models to define the mutant-specific features of NRAS that facilitate BRAF interactions (Aim 1) and how the structural determinants of different NRAS mutant-BRAF interactions influence BRAF inhibitor sensitivity (Aim 2). Successful completion of these studies will enhance my knowledge of structural biology, therapeutic development, and mouse models of cancer. I will also identify mutant-specific NRAS-BRAF interfaces to guide the design of novel therapeutic approaches for NRAS-mutant cancers and provide information relevant to the clinical implementation of next-generation RAF inhibitors.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
