Kirsten rat sarcoma virus oncogene homolog (KRAS) G12D and G12V mutants (KRAS G12D/V)

KRAS is a small GTPase that acts as a molecular switch in the MAPK/ERK and PI3K/AKT signaling pathways, regulating essential cellular processes such as growth, proliferation, and survival. The G12D and G12V mutations are among the most frequent oncogenic drivers in human cancers, particularly in pancreatic, colorectal, and lung malignancies. These mutations impair the intrinsic GTPase activity of KRAS and its sensitivity to GTPase-activating proteins (GAPs), locking the protein in a constitutive 'on' state that promotes uncontrolled tumor growth. While KRAS was historically considered 'undruggable' due to its high affinity for GTP and lack of accessible binding pockets, recent breakthroughs have led to the development of allele-specific inhibitors like MRTX1133 for G12D and pan-RAS inhibitors like RMC-6236 that target multiple mutants including G12V. Therapeutic strategies now focus on non-covalent binding to the switch II pocket or utilizing proteolysis-targeting chimeras (PROTACs) to degrade the mutant protein. Clinical management of KRAS-mutant cancers increasingly relies on molecular profiling to match patients with these emerging targeted therapies.

Other names

KRAS proto-oncogene, GTPaseK-Ras 2p21 proteinKRAS2RASK2Kirsten rat sarcoma viral oncogene homolog

Inhibition of the KRAS protein by binding to the switch II pocket in either the active (GTP-bound) or inactive (GDP-bound) state, preventing interaction with downstream effectors like RAF, or through targeted protein degradation.