Ning, Wenjuan; Yang, Zhang; Kocher, Gregor J; Dorn, Patrick; Peng, Ren-Wang (2022). A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished. Cancers, 14(2) MDPI AG 10.3390/cancers14020390
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KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable-that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions.
Item Type: |
Journal Article (Review Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Ning, Wenjuan, Yang, Zhang (B), Kocher, Gregor, Dorn, Patrick, Peng, Ren-Wang |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2072-6694 |
Publisher: |
MDPI AG |
Language: |
English |
Submitter: |
Thomas Michael Marti |
Date Deposited: |
20 Dec 2022 11:35 |
Last Modified: |
29 Mar 2023 23:38 |
Publisher DOI: |
10.3390/cancers14020390 |
PubMed ID: |
35053550 |
Uncontrolled Keywords: |
KRAS-mutant cancer KRASG12C KRASG12C inhibitors acquired resistance combination therapy |
BORIS DOI: |
10.48350/175976 |
URI: |
https://boris.unibe.ch/id/eprint/175976 |
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