Targeting KRAS in cancer Review
| Authors: | Singhal, A.; Li, B. T.; O’Reilly, E. M. |
| Review Title: | Targeting KRAS in cancer |
| 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. © Springer Nature America, Inc. 2024. |
| Keywords: | genetics; mutation; review; pancreatic neoplasms; allele; carcinoma, non-small-cell lung; lung neoplasms; alleles; lung tumor; cancer cell; pancreas tumor; k ras protein; protein p21; proto-oncogene proteins p21(ras); kras protein, human; non small cell lung cancer; genetic resistance; humans; human; malignant neoplasm; sotorasib; adagrasib |
| Journal Title: | Nature Medicine |
| Volume: | 30 |
| Issue: | 4 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-04-01 |
| Start Page: | 969 |
| End Page: | 983 |
| Language: | English |
| DOI: | 10.1038/s41591-024-02903-0 |
| PUBMED: | 38637634 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Eileen O'Reilly -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work