RAS-targeted therapies: is the undruggable drugged?

Nature Reviews. Drug Discovery
Amanda R MooreShiva Malek

Abstract

RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed 'undruggable'. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRASG12C, we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies.

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Methods Mentioned

BETA
GTPase
nucleotide exchange
xenograft
xenografts
biopsies
transgenic

Clinical Trials Mentioned

NCT03600883
NCT03785249
NCT04006301
NCT04165031
NCT04111458
NCT03634982
NCT03114319
NCT02383927
NCT03118817
NCT02607813

Software Mentioned

ICECREAM
Revolution

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