Abstract

RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

Highlights

  • HRAS was first regarded as oncogene due to a singlepoint mutation in 1982

  • Great progress has been made in the past few years, especially with the approval of Lumakras in treatment of K­ RASG12C-mutant Non-small-cell lung carcinoma (NSCLC) patients who have received at least one prior systemic therapy, this approval ended the history of no drug in clinic for RAS mutation

  • One potential direction is the combination of several inhibitors

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Summary

Introduction

HRAS was first regarded as oncogene due to a singlepoint mutation in 1982. Subsequently, NRAS and KRAS were identified quickly [1]. Combined inhibition of MEK and SHP2 showed high efficiency in engineered or xenograft KRAS-mutant pancreas, ovarian, and lung cancer [81, 83–85], overcoming the rapid resistance to MEK inhibitor as a single therapy. Based on ARS1620, a novel-generation ­KRASG12C inhibitor, ARS3248 (JNJ-74699157) is undergoing clinical study of its safety and antitumor activity in patients with advanced solid tumors harboring ­KRASG12C mutation (NCT04006301).

Results
Conclusion

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