The RAS Superfamily of Small GTPases in Cancer
Year: 2020
Type: dissertation
Abstract: Contained within the Ras superfamily of small GTPases are several important oncogenes. RAS is the most frequently mutated oncogene in human cancers, and mutant RAS signaling is responsible for a multitude of oncogenic signals leading to uncontrolled cell growth and proliferation. Since its discovery in 1982, significant advances have been made in understanding its function, but despite decades of research, there is still no effective anti-RAS therapy. The RHOA gene encodes a protein homologous to RAS that regulates actin dynamics, cytoskeletal reorganization, cell migration, and cell division. However, despite its identification as a RAS-related protein, no mutations in RHOA had been described in human cancers until recent cancer genome sequencing studies uncovered novel hotspot mutations in RHOA. My dissertation examines the roles of these two proteins in cancer. Of the RAS oncogenes, KRAS is the most frequently mutated in pancreatic cancer, with over 90% of PDAC tumors harboring an activating KRAS mutation. The oncogenic transcription factor MYC cooperates with activated KRAS to drive pancreatic cancer, and MYC is required for tumor maintenance. Signaling pathways downstream of activated KRAS significantly stabilize MYC protein in PDAC, but there are important regulatory pathways that have not yet been identified. The first part of my doctoral work focuses on discovering novel regulators of MYC protein stability in PDAC. We have developed a MYC degradation reporter, performed a small-molecule kinase inhibitor screen, and identified ERK5 and CDK9 as novel regulators of MYC protein stability. In 2014, three independent groups identified recurring RHOA mutations in diffuse gastric cancer (DGC) and some peripheral T cell lymphomas. Interestingly, these mutations were not at the same hotspots that are found in RAS. The effect of these mutations on the biochemistry and signaling properties of RHOA are unknown, and some even suggest a loss-of-function, rather than a gain-of-function role in cancer. The second part of my doctoral work focuses on elucidating the role of the most frequent RHOA mutation, Y42C, in DGC progression. We have characterized the biochemical differences of RHOA Y42C, generated a RHOA Y42C knock-in mouse and murine gastric organoids, and identified FAK as a potential therapeutic target for patients with RHOA-mutant diffuse gastric cancer.
DOI: 10.17615/ahf8-gx71
Author: Blake, Devon Rowland
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3182075994