Kirsten rat sarcoma virus oncogene homolog G12D mutant (KRAS G12D) (KRAS G12D)

KRAS G12D is a specific missense mutation in the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene, where the glycine at position 12 is replaced by aspartic acid [6, 11]. This mutation impairs the intrinsic GTPase activity of the KRAS protein, locking it in a constitutively active, GTP-bound state that drives uncontrolled cell proliferation and survival through the MAPK/ERK and PI3K/AKT signaling pathways [1, 6]. KRAS G12D is the most prevalent KRAS mutation in human cancers, particularly dominant in pancreatic ductal adenocarcinoma (~40%), colorectal cancer (~12%), and non-small cell lung cancer [3, 12, 18]. Historically considered "undruggable" due to its high affinity for GTP and lack of deep binding pockets, recent breakthroughs have led to the development of allele-specific inhibitors like MRTX1133 and HRS-4642, as well as degraders like ASP3082 [4, 6, 9]. These therapeutic agents aim to selectively inhibit the mutant protein's activity or induce its degradation, thereby suppressing tumor growth while sparing wild-type KRAS function [5, 12]. Clinical challenges include the emergence of resistance through bypass signaling and the need for combination strategies to enhance efficacy [14, 17].

Other names

KRAS G12DK-Ras G12Dp21 G12DKRAS2 G12DKirsten rat sarcoma 2 viral oncogene homolog G12DKRAS proto-oncogene, GTPase G12D

Non-covalent inhibition of the switch II pocket, targeted protein degradation (PROTAC), and inhibition of nucleotide exchange.