Expanding the reach of precision oncology by drugging all KRAS mutants Review


Authors: Hofmann, M. H.; Gerlach, D.; Misale, S.; Petronczki, M.; Kraut, N.
Review Title: Expanding the reach of precision oncology by drugging all KRAS mutants
Abstract: KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRAS(G12C) inhibitors are currently changing the treatment paradigm for patients with KRAS(G12C)-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRAS(G12D)-, KRAS(G12V)-, KRAS(G13D)-, KRAS(G12R)-, and KRAS(G12A)-mutant or KRAS wild-typeamplified cancers, as well as cancers with acquired resistance to KRAS(G12C) inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. Significance: Mutant-selective KRAS(G12C) inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRASdriven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.
Keywords: ras; solid tumors; cell-proliferation; mek inhibitor; genomic alterations; kras(g12c); amg 510; colorectal-cancer crc; adagrasib mrtx849; krystal-1 activity
Journal Title: Cancer Discovery
Volume: 12
Issue: 4
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2022-04-01
Start Page: 924
End Page: 937
Language: English
ACCESSION: WOS:000795657900001
DOI: 10.1158/2159-8290.Cd-21-1331
PROVIDER: wos
PUBMED: 35046095
Notes: Review -- Source: Wos
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  1. Sandra Misale
    17 Misale