Kirsten rat sarcoma viral proto-oncogene (KRAS) mutant signaling complex (KRAS-mutant complex)

KRAS-mutant signaling complexes are multi-protein assemblies centered around mutated forms of the KRAS GTPase, which serves as a critical molecular switch in cellular signaling pathways (UniProt P01116). In healthy cells, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state; however, oncogenic mutations (e.g., G12C, G12D, G12V) impair GTP hydrolysis or accelerate nucleotide exchange, leading to a constitutively active state (Nature Reviews Cancer, 2022). These complexes involve the recruitment of guanine nucleotide exchange factors (GEFs) like SOS1 and downstream effectors such as RAF, PI3K, and RalGDS, which drive uncontrolled cell growth, survival, and metastasis (Journal of Hematology & Oncology, 2021). Historically considered undruggable, these complexes are now targeted by allele-specific covalent inhibitors like sotorasib and adagorasib, which trap the KRAS G12C mutant in its inactive GDP-bound conformation (NEJM, 2021). Emerging therapeutic strategies also include RAS(ON) inhibitors that target the active GTP-bound complex and inhibitors of upstream regulators like SHP2 and SOS1 to disrupt the assembly of the signaling hub (Cancer Discovery, 2022). Despite clinical success, the dynamic nature of these complexes often leads to adaptive resistance through secondary mutations or the activation of bypass signaling pathways, necessitating the development of combination therapy regimens (Nature, 2020).

Other names

KRAS signalosomeKRAS-effector complexKRAS-SOS1 complexKRAS-RAF complexMutant KRAS signaling hub

Covalent inhibition of the KRAS G12C mutant in the inactive GDP-bound state; disruption of the KRAS-SOS1 interaction to inhibit nucleotide exchange; direct inhibition of the active GTP-bound KRAS (RAS-ON) to prevent effector engagement; and inhibition of the SHP2 phosphatase to reduce RAS activation.