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Review
. 2025 Jul 3;15(7):1325-1349.
doi: 10.1158/2159-8290.CD-25-0349.

Response and Resistance to RAS Inhibition in Cancer

Richard Y Ebright  1   2   3 , Julien Dilly  1   2   3 , Alice T Shaw  1   2 , Andrew J Aguirre  1   2   3
Affiliations
Review

Response and Resistance to RAS Inhibition in Cancer

Richard Y Ebright et al. Cancer Discov. .

Abstract

RAS inhibition has the potential to transform cancer treatment for many patients. The landscape of RAS inhibitor therapies is rapidly evolving, with two mutant-selective KRAS inhibitors now approved and multiple other mutant-selective, pan-KRAS, and pan-RAS inhibitors in development. However, monotherapy efficacy has been limited by primary and acquired resistance. In this article, we review preclinical and clinical data on RAS inhibition in cancer and describe multiple genetic and nongenetic mechanisms of resistance. Moreover, we highlight future opportunities for the design of rational combination therapy strategies, which will ultimately be needed to overcome resistance and enhance the efficacy of these promising treatments.

Significance: RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance. Development of best-in-class inhibitors, with optimal potency, selectivity, and pharmacokinetic properties, as well as effective and tolerable combination therapies will be needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy.

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Conflict of interest statement

Conflict-of-interest statement:

R.Y.E. has consulted for Nextech Invest, Third Rock Ventures, and Luma Group. A.T.S. has consulted for Pfizer, Nuvalent, Tango, Triana, Novartis, Rigel, Nextech and EcoR1. A.T.S. was formerly employed by Novartis. A.J.A. has consulted for Anji Pharmaceuticals, Affini-T Therapeutics, Arrakis Therapeutics, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Celex Oncology, Incyte, Kestrel Therapeutics, Merck & Co., Inc., Mirati Therapeutics, Nimbus Therapeutics, Oncorus, Inc., Plexium, Quanta Therapeutics, Revolution Medicines, Reactive Biosciences, Riva Therapeutics, Servier Pharmaceuticals, Syros Pharmaceuticals, Taiho Pharmaceuticals, T-knife Therapeutics, Third Rock Ventures, and Ventus Therapeutics. A.J.A. holds equity in Riva Therapeutics and Kestrel Therapeutics. A.J.A. has research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Deerfield, Inc., Eli Lilly, Mirati Therapeutics, Nimbus Therapeutics, Novartis, Novo Ventures, Revolution Medicines, and Syros Pharmaceuticals.

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