FOXP2/SOS1/AKT negative feedback loop inhibits cell proliferation in KRAS-mutant colorectal cancer

FOXP2, a member of the Forkhead box transcription factor family, has been implicated in diverse biological processes and malignancies. However, its role in colorectal cancer (CRC), particularly in the context of KRAS mutations, remains poorly defined. Here, we analyzed FOXP2 expression in CRC datasets and clinical specimens, and conducted functional assays-including colony formation, cell viability, EdU incorporation, and cell cycle analysis-in KRAS-mutant CRC cell lines with FOXP2 overexpression or knockdown. Western blotting, dual-luciferase reporter assays, and in vivo xenograft models were used to explore the underlying mechanisms. FOXP2 was significantly downregulated in CRC tissues and its high expression correlated with favorable prognosis in KRAS-mutant patients. Functionally, FOXP2 overexpression suppressed cell proliferation, induced G0/G1-phase arrest, and inhibited PI3K/AKT signaling. Mechanistically, FOXP2 transcriptionally repressed SOS1, thereby attenuating downstream AKT activation. Notably, AKT activation enhanced FOXP2 expression, indicating a FOXP2/SOS1/AKT negative feedback loop. Collectively, our findings suggest that FOXP2 inhibits proliferation in KRAS-mutant CRC by suppressing SOS1-mediated PI3K/AKT signaling, and may serve as a prognostic biomarker and potential therapeutic target in KRAS-driven CRC.