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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 KRASG12C to 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-KRASG12D mice. 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.

SUBMITTER: Pang X

PROVIDER: S-EPMC5680709 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Defeat mutant KRAS with synthetic lethality.

Pang Xiufeng X Liu Mingyao M

Small GTPases 20160727 4

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 ...[more]

PMID: 27463838

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Project description:BackgroundOncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge in the clinic. Increasing evidence suggests that aberrant metabolism plays a central role in KRAS-driven oncogenic transformation. The aim of this study is to identify selective metabolic dependency induced by mutant KRAS and to exploit it for the treatment of the disease.MethodWe performed an integrated analysis of RNAi- and CRISPR-based functional genomic datasets (n = 5) to identify novel genes selectively required for KRAS-mutant cancer. We further screened a customized library of chemical inhibitors for candidates that are synthetic lethal with NOP56 depletion. Functional studies were carried out by genetic knockdown using siRNAs and shRNAs, knockout using CRISPR/Cas9, and/or pharmacological inhibition, followed by cell viability and apoptotic assays. Protein expression was determined by Western blot. Metabolic ROS was measured by flow cytometry-based quantification.ResultsWe demonstrated that nucleolar protein 5A (NOP56), a core component of small nucleolar ribonucleoprotein complexes (snoRNPs) with an essential role in ribosome biogenesis, confers a metabolic dependency by regulating ROS homeostasis in KRAS-mutant lung cancer cells and that NOP56 depletion causes synthetic lethal susceptibility to inhibition of mTOR. Mechanistically, cancer cells with reduced NOP56 are subjected to higher levels of ROS and rely on mTOR signaling to balance oxidative stress and survive. We also discovered that IRE1α-mediated unfolded protein response (UPR) regulates this process by activating mTOR through p38 MAPK. Consequently, co-targeting of NOP56 and mTOR profoundly enhances KRAS-mutant tumor cell death in vitro and in vivo.ConclusionsOur findings reveal a previously unrecognized mechanism in which NOP56 and mTOR cooperate to play a homeostatic role in the response to oxidative stress and suggest a new rationale for the treatment of KRAS-mutant cancers.

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Defeat mutant KRAS with synthetic lethality.

Publications

Defeat mutant KRAS with synthetic lethality.

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