title: Improving Prospects for Targeting RAS.
abstract: RAS mutations are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors and around a fifth of common myeloid malignancies, but they have evaded therapeutic interventions, despite being the focus of intense research over the last three decades. Recent discoveries lend new understanding about the structure, function, and signaling of RAS and have opened new avenues for development of much needed new therapies. We discuss the various approaches under investigation to target mutant RAS proteins. The recent development of direct RAS inhibitors specific to KRAS G12C mutations represents a landmark discovery that promises to change the perception about RAS's druggability. Multiple clinical trials targeting synthetically lethal partners and/or downstream signaling partners of RAS are underway. Novel inhibitors targeting various arms of RAS processing and signaling have yielded encouraging results in the laboratory, but refinement of the drug-like properties of these molecules is required before they will be ready for the clinic.
authors.affiliation: Harshabad Singh and Bruce A. Chabner, Massachusetts General Hospital Cancer Center; Harshabad Singh, Dana-Farber Cancer Institute; and Dan L. Longo, Brigham and Women's Hospital, Boston, MA.
authors.forename: Harshabad
authors.initials: H
authors.lastname: Singh
authors.affiliation: Harshabad Singh and Bruce A. Chabner, Massachusetts General Hospital Cancer Center; Harshabad Singh, Dana-Farber Cancer Institute; and Dan L. Longo, Brigham and Women's Hospital, Boston, MA.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Harshabad Singh and Bruce A. Chabner, Massachusetts General Hospital Cancer Center; Harshabad Singh, Dana-Farber Cancer Institute; and Dan L. Longo, Brigham and Women's Hospital, Boston, MA. bchabner@partners.org.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Chabner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D011905:Genes, ras; D006801:Humans; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C000599897:KRAS4B protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins