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The current state of the art and future trends in RAS-targeted cancer therapies

Nature Reviews Clinical Oncology volume 19, pages 637–655 (2022)Cite this article

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Abstract

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered ‘undruggable’ owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRASG12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

Key points

  • Owing to intrinsic and extrinsic factors, KRAS and other RAS isoforms have until recently been impervious to targeting with small-molecule inhibitors.

  • Inhibitors of the KRASG12C variant constitute a potential breakthrough in the treatment of many cancer types, particularly non-small-cell lung cancer, for which such an agent has been approved by the FDA.

  • Several forms of resistance to KRAS inhibitors have been defined, including primary, adaptive and acquired resistance; these resistance mechanisms are being targeted in studies that combine KRAS inhibitors with inhibitors of horizontal or vertical signalling pathways.

  • Mutant KRAS has important effects on the tumour microenvironment, including the immunological milieu; these effects must be considered to fully understand resistance to KRAS inhibitors and when designing novel treatment strategies.

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Fig. 1: The RAS signalling pathway and therapeutic approaches to target this pathway in cancer.
Fig. 2: The prevalence of KRAS, NRAS and HRAS mutations across cancer types.
Fig. 3: The influence of mutant KRAS on the tumour immune microenvironment.

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  1. Division of Hematology and Medical Oncology, Department of Medicine, Laura and Isaac Perlmutter Cancer Center, New York University (NYU) Grossman School of Medicine, NYU Langone Health, New York, NY, USA

    Salman R. Punekar, Vamsidhar Velcheti, Benjamin G. Neel & Kwok-Kin Wong

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V.V. has received fees for consulting or serving on advisory boards from Amgen, AstraZeneca, Bristol Myers Squibb (BMS), EMD Serono, Foundation Medicine, GlaxoSmithKline, Iteos Therapeutics, Merck, Novartis and Novocure. B.G.N. is a co-founder, holds equity in and receives consulting fees from Lighthorse Therapeutics and Navire Pharmaceuticals; is a co-founder and holds equity in Northern Biologics; is a scientific advisory board (SAB) member for, holds equity in and receives consulting fees from Arvinas; and is an SAB member for and holds equity in Recursion Pharma. K.-K.W. is a co-founder of and holds equity in G1 Therapeutics; has received grants from Alkermes, Ansun, AstraZeneca, BMS, Dracen, Merus, Mirati, Takeda and Tvardi; grants and personal fees from Delfi, Janssen, Pfizer and Zentalis; personal fees from Navire, Prelude and Recursion; and grants from Ono outside the submitted work. S.R.P. declares no competing interests.

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Punekar, S.R., Velcheti, V., Neel, B.G. et al. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol 19, 637–655 (2022). https://doi.org/10.1038/s41571-022-00671-9

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