title: Defeat mutant KRAS with synthetic lethality.
abstract: Ras proteins are considered as the founding members of a large superfamily of small GTPases that control fundamental cellular functions. Mutationally activated RAS genes were discovered in human cancer cells more than 3 decades ago, but intensive efforts on Ras structure, biochemistry, function and signaling continue even now. Because mutant Ras proteins are inherently difficult to inhibit and have yet been therapeutically conquered, it was designated as "the Everest of oncogenes" in the cancer genome landscape, further promoting a "renaissance" in RAS research. Different paths to directly or indirectly targeting mutant Ras signaling are currently under investigation in the hope of finding an efficacious regimen. Inhibitors directly binding to KRASG12Cto block its downstream signaling have been revealed, supporting the notion of Ras' druggability. An alternative indirect approach by targeting synthetic lethal interactors of mutant RAS is underway. We recently employed a synthetic lethal drug screen plus a combinatorial strategy using a panel of clinical agents and discovered that KRAS-mutant cancers were fragile to the combined inhibition of polo-like kinase 1 (Plk1) and RhoA/Rho kinase (ROCK). The combined regimen of BI-2536 (a Plk1 inhibitor) and fasudil (a ROCK inhibitor) promoted a significant inhibition of patient-derived lung cancer xenografts and prolonged the survival of LSL-KRASG12Dmice. In this commentary, we will summarize the state-of-the art for the direction of synthetic lethality, and also speculate on the future development of this approach.
authors.affiliation: a Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai , China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
authors.affiliation: a Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai , China.|b Institute of Biosciences and Technology , Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center , Houston , TX , USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics*; D034622:RNA Interference; D000072020:Synthetic Lethal Mutations
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutations; Ras; combination therapy; synthetic lethal screens; synthetic lethality