Therapeutic strategies to target RAS-mutant cancers

Abstract

RAS genes are the most commonly mutated oncogenes in cancer, but effective therapeutic strategies to target RAS-mutant cancers have proved elusive. A key aspect of this challenge is the fact that direct inhibition of RAS proteins has proved difficult, leading researchers to test numerous alternative strategies aimed at exploiting RAS-related vulnerabilities or targeting RAS effectors. In the past few years, we have witnessed renewed efforts to target RAS directly, with several promising strategies being tested in clinical trials at different stages of completion. Important advances have also been made in approaches designed to indirectly target RAS by improving inhibition of RAS effectors, exploiting synthetic lethal interactions or metabolic dependencies, using therapeutic combination strategies or harnessing the immune system. In this Review, we describe historical and ongoing efforts to target RAS-mutant cancers and outline the current therapeutic landscape in the collective quest to overcome the effects of this crucial oncogene.

Key points

  • RAS is the most commonly mutated oncogene in cancer.

  • Direct inhibition of oncogenic RAS has proved difficult, hindering the development of effective therapies for RAS-mutant cancers.

  • Renewed efforts to target mutant RAS directly have yielded promising efficacy outcomes in preclinical studies.

  • Targeting key effector pathways or vulnerabilities in RAS-mutant cancers offers a promising alternative therapeutic approach.

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Fig. 1: RAS structure and regulation.
Fig. 2: Direct inhibition of RAS function.
Fig. 3: Approaches to inhibiting RAS function.
Fig. 4: Inhibitors of RAF–MEK–ERK currently under clinical evaluation.

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Acknowledgements

The work of R.B.C. is supported by US National Institutes of Health (NIH)-National Cancer Institute (NCI) Gastrointestinal Cancer SPORE P50 CA127003, R01CA208437 and U54CA224068 and a Stand Up To Cancer (SU2C) Colorectal Dream Team Translational Research Grant (grant number SU2C-AACR-DT22-17). Research grants are administered by the American Association of Cancer Research, the scientific partner of SU2C.

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M.B.R. and R.B.C. contributed equally to all aspects of the preparation of this manuscript.

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Correspondence to Ryan B. Corcoran.

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R.B.C. has received consulting fees from Amgen, Astex, Avidity, Bristol-Myers Squibb, FOG Pharma, Genentech, LOXO, Merrimack, N-of-One, Roche, Roivant, Shire, Symphogen, Taiho and Warp Drive Bio, as well as research support from AstraZeneca and Sanofi. M.B.R. declares no competing interest.

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The RAS initiative: https://www.cancer.gov/research/key-initiatives/rasUS National Institutes of Health ClinicalTrials.gov database: https://www.clinicaltrials.gov

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Ryan, M.B., Corcoran, R.B. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol 15, 709–720 (2018). https://doi.org/10.1038/s41571-018-0105-0

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