Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

被引：205

作者：

Hofmann, Marco H. ^{[1
]}

Gerlach, Daniel ^{[1
]}

Misale, Sandra ^{[2
]}

Petronczki, Mark ^{[1
]}

Kraut, Norbert ^{[1
]}

机构：

[1] Boehringer Ingelheim RCV GmbH & Co KG, Discovery Res, Vienna, Austria

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

来源：

CANCER DISCOVERY | 2022年 / 12卷 / 04期

关键词：

COLORECTAL-CANCER CRC; MEK INHIBITOR; ADAGRASIB MRTX849; SOLID TUMORS; GENOMIC ALTERATIONS; CELL-PROLIFERATION; KRYSTAL-1; ACTIVITY; AMG; 510; RAS; KRAS(G12C);

D O I：

10.1158/2159-8290.CD-21-1331

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：924 / 937

页数：14

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