Kirsten rat sarcoma virus oncogene homolog–Son of Sevenless homolog 1–Mitogen-activated protein kinase pathway (KRAS–SOS1–MAPK pathway)

The KRAS–SOS1–MAPK pathway is a central signaling axis that governs essential cellular processes such as growth, proliferation, and survival [1]. In this cascade, the Son of Sevenless homolog 1 (SOS1) acts as a guanine nucleotide exchange factor that catalyzes the transition of the KRAS GTPase from an inactive GDP-bound state to an active GTP-bound state [2]. Once activated, KRAS triggers the mitogen-activated protein kinase (MAPK) cascade, a series of phosphorylation events involving RAF, MEK, and ERK kinases [3]. This pathway is frequently hyperactivated in human cancers, most commonly through oncogenic mutations in the KRAS gene that lock the protein in its active conformation [1, 4]. Such dysregulation is a primary driver in aggressive malignancies, including pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer [4]. Therapeutic interventions target various nodes of this pathway, including direct KRAS G12C inhibitors, SOS1 inhibitors that disrupt the KRAS-SOS1 interaction, and downstream MEK or ERK inhibitors [3, 5]. While these drugs have shown clinical efficacy, the pathway often develops resistance through compensatory feedback loops or secondary mutations, necessitating the development of combination therapies [5, 6].

Other names

RAS-RAF-MEK-ERK pathwayMAPK/ERK pathwayRAS-MAPK signaling axisMitogen-activated protein kinase signaling cascade

Covalent inhibition of KRAS G12C, inhibition of SOS1-KRAS protein-protein interaction, allosteric inhibition of MEK1/2, and ATP-competitive inhibition of ERK1/2.