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From bench to bedside: current development and emerging trend of KRAS-targeted therapy

Acta Pharmacologica Sinica volume 45, pages 686–703 (2024)Cite this article

Abstract

Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRASG12C mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy. So far, two small molecule inhibitors sotorasib and adagrasib targeting KRASG12C have received accelerated approval for the treatment of non-small cell lung cancer (NSCLC) harboring KRASG12C mutations. In recent years, rapid progress has been achieved in the KRAS-targeted therapy field, especially the exploration of KRASG12C covalent inhibitors in other KRASG12C-positive malignancies, novel KRAS inhibitors beyond KRASG12C mutation or pan-KRAS inhibitors, and approaches to indirectly targeting KRAS. In this review, we provide a comprehensive overview of the molecular and mutational characteristics of KRAS and summarize the development and current status of covalent inhibitors targeting the KRASG12C mutation. We also discuss emerging promising KRAS-targeted therapeutic strategies, with a focus on mutation-specific and direct pan-KRAS inhibitors and indirect KRAS inhibitors through targeting the RAS activation-associated proteins Src homology-2 domain-containing phosphatase 2 (SHP2) and son of sevenless homolog 1 (SOS1), and shed light on current challenges and opportunities for drug discovery in this field.

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Fig. 1: Overview of advances in KRAS-targeted therapy inhibitors.
Fig. 2: Structure of KRAS protein and mutation frequency in human cancer.
Fig. 3: Chemical structures of representative KRAS-targeted therapeutic inhibitors.

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Acknowledgements

This research was supported by grants from the National Natural Science Foundation of China (82273948), High-level Innovative Research Institute (2021B0909050003), State Key Laboratory of Drug Research (SKLDR-2023-TT-01 and SIMM2205KF-09).

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  1. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Yi Chen, Qiu-pei Liu, Hua Xie & Jian Ding

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yi Chen, Hua Xie & Jian Ding

  3. Department of Chemical and Environment Engineering, Science and Engineering Building, The University of Nottingham Ningbo China, Ningbo, 315100, China

    Qiu-pei Liu

  4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Hua Xie

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Chen, Y., Liu, Qp., Xie, H. et al. From bench to bedside: current development and emerging trend of KRAS-targeted therapy. Acta Pharmacol Sin 45, 686–703 (2024). https://doi.org/10.1038/s41401-023-01194-4

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