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Targeting KRAS in cancer

Nature Medicine volume 30, pages 969–983 (2024)Cite this article

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Abstract

RAS family variants—most of which involve KRAS—are the most commonly occurring hotspot mutations in human cancers and are associated with a poor prognosis. For almost four decades, KRAS has been considered undruggable, in part due to its structure, which lacks small-molecule binding sites. But recent developments in bioengineering, organic chemistry and related fields have provided the infrastructure to make direct KRAS targeting possible. The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents—sotorasib and adagrasib. Inhibitors targeting other variants beyond G12C have shown preliminary antitumor activity in highly refractory malignancies such as pancreatic cancer. Herein, we outline RAS pathobiology with a focus on KRAS, illustrate therapeutic approaches across a variety of malignancies, including emphasis on the ‘on’ and ‘off’ switch allele-specific and ‘pan’ RAS inhibitors, and review immunotherapeutic and other key combination RAS targeting strategies. We summarize mechanistic understanding of de novo and acquired resistance, review combination approaches, emerging technologies and drug development paradigms and outline a blueprint for the future of KRAS therapeutics with anticipated profound clinical impact.

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Fig. 1: Regulation of KRAS and signal transduction pathways.
Fig. 2: RAS mutations in cancer.
Fig. 3: Overcoming resistance to RAS inhibitors with combination approaches.

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Acknowledgements

Cancer Center Support Grant/Core Grant P30 CA008748. NCI/NIH P50 CA257881-01A1. NCI/NIH K12 CA184746.

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Authors and Affiliations

  1. Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Anupriya Singhal & Eileen M. O’Reilly

  2. David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Anupriya Singhal & Eileen M. O’Reilly

  3. Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Bob T. Li

  4. Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Bob T. Li

  5. Weill Cornell Medicine, New York, NY, USA

    Bob T. Li & Eileen M. O’Reilly

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Correspondence to Eileen M. O’Reilly.

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Competing interests

E.O.R. has received institutional research funding from Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Digestive Care, Revolution Medicine. Consulting/DSMB: Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse) and Servier (Spouse). B.T.L. serves as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech and Lilly. B.T.L. has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, Revolution Medicine, and Lilly. B.T.L. received academic travel support from Amgen. B.T.L. is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. A.S. declares no competing interests.

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Nature Medicine thanks Grainne O’Kane, Jayesh Desai, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Karen O’Leary, in collaboration with the Nature Medicine team.

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Supplementary information

Supplementary Table 1

Frequency of acquired resistance mutations in MAPK pathway genes in recent clinical datasets.

Supplementary Table 2

Trials of combination therapy with KRAS inhibitors.

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Singhal, A., Li, B.T. & O’Reilly, E.M. Targeting KRAS in cancer. Nat Med 30, 969–983 (2024). https://doi.org/10.1038/s41591-024-02903-0

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