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Drugging the Undruggable: Advances on RAS Targeting in Cancer

Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK
Department of Medical Oncology, Imperial College Healthcare NHS Trust, London W2 1NY, UK
Lung Cancer Group, Institute of Cancer Research, London SW3 6JB, UK
Authors to whom correspondence should be addressed.
Academic Editor: Esther Castellano-Sánchez
Received: 20 May 2021 / Revised: 2 June 2021 / Accepted: 4 June 2021 / Published: 10 June 2021
(This article belongs to the Special Issue RAS Signaling in Health and Disease)
Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms. View Full-Text
Keywords: RAS; KRAS-G12C; oncogene; cancer; targeted therapy RAS; KRAS-G12C; oncogene; cancer; targeted therapy
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MDPI and ACS Style

Molina-Arcas, M.; Samani, A.; Downward, J. Drugging the Undruggable: Advances on RAS Targeting in Cancer. Genes 2021, 12, 899.

AMA Style

Molina-Arcas M, Samani A, Downward J. Drugging the Undruggable: Advances on RAS Targeting in Cancer. Genes. 2021; 12(6):899.

Chicago/Turabian Style

Molina-Arcas, Miriam, Amit Samani, and Julian Downward. 2021. "Drugging the Undruggable: Advances on RAS Targeting in Cancer" Genes 12, no. 6: 899.

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