Disrupting the KRAS–SOS1 protein–protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy

Abstract

Oncogenic KRAS signaling is among the most prevalent drivers in human cancer, yet durable pathway suppression has historically been limited by incomplete target coverage, toxicity constraints for downstream kinase inhibitors, and rapid adaptive rewiring through receptor tyrosine kinase (RTK) feedback. A renewed focus on the KRAS activation cycle has positioned SOS1-an RTK-coupled guanine nucleotide exchange factor-as an attractive upstream node to modulate KRAS output across multiple alleles. By disrupting the KRAS-SOS1 protein-protein interaction (PPI) or otherwise limiting SOS1-mediated nucleotide exchange, SOS1-directed agents reduce RAS-GTP formation and suppress Mitogen-Activated Protein Kinase (MAPK) signaling, while also attenuating feedback-driven rebound that commonly follows MEK/ERK inhibition or allele-specific KRAS targeting. In this review, we summarize the structural and mechanistic basis of RAS-SOS engagement, the emergence of a druggable pocket on SOS1 exploited by modern inhibitors, and the evolution from peptide/interface-mimic approaches to potent small-molecule PPI disruptors. We synthesize key pharmacology across tool compounds and clinical candidates, emphasizing biomarker-linked pharmacodynamic readouts (RAS-GTP and Phosphorylated extracellular signal-regulated kinase (pERK)), context dependence (KRAS allele, RTK tone, and pathway baseline), and on-target validation strategies spanning biophysics, structural biology, and cellular engagement. We then discuss why SOS1 inhibitors act as "multiplier" drugs in rational combinations-particularly with MEK inhibitors and KRAS (G12C) inhibitors-outline expected resistance routes and candidate predictive biomarkers, and review the current clinical landscape for SOS1 inhibitors and combination trial design. Finally, we highlight emerging directions including next-generation, brain-penetrant chemistry and event-driven SOS1 degraders, and propose priorities for translating upstream exchange control into durable patient benefit.