Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

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.