Son of Sevenless homolog 1 (SOS1) and Kirsten rat sarcoma virus oncogene homolog (KRAS) protein-protein interaction (SOS1::KRAS PPI)

The Son of Sevenless homolog 1 (SOS1) and Kirsten rat sarcoma virus oncogene homolog (KRAS) protein-protein interaction is a fundamental regulatory mechanism in the RAS/MAPK signaling pathway. SOS1 serves as a guanine nucleotide exchange factor (GEF) that catalyzes the release of GDP from KRAS, allowing GTP to bind and activate the protein for downstream signaling (UniProt Q07889, P01116). In many human malignancies, KRAS mutations lock the protein in a constitutively active state or increase its sensitivity to GEF-mediated activation, driving oncogenesis (Hofmann et al., 2021). Targeting the SOS1::KRAS interaction has emerged as a pan-KRAS therapeutic strategy, as inhibiting SOS1 can reduce the activation of various KRAS mutants by preventing the nucleotide exchange required for their signaling cycles (Hillig et al., 2019). This approach is particularly valuable for targeting KRAS mutations that lack direct inhibitors, such as G12D or G12V, and for overcoming resistance to G12C-specific inhibitors. Small molecule inhibitors like BI-1701963 and MRTX0902 bind to SOS1 to disrupt this interaction, effectively shifting the equilibrium toward the inactive KRAS-GDP state. These agents are currently being evaluated in clinical trials, both as monotherapies and in combination with other MAPK pathway inhibitors, to treat KRAS-driven cancers including pancreatic, colorectal, and lung adenocarcinoma (ClinicalTrials.gov NCT04111458).

Other names

SOS1-KRAS interactionSOS1/KRAS complexSOS1-mediated KRAS activation

Inhibition of the SOS1-mediated nucleotide exchange on KRAS by binding to SOS1 and preventing the formation of the SOS1::KRAS complex, thereby maintaining KRAS in its inactive GDP-bound state (Hofmann et al., 2021; Hillig et al., 2019).