GEOTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312194GEOGSEfalseMEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RNASeq_HCT116]AXIN1 is a central regulatory hub of many oncogenic pathways in colorectal cancer (CRC). As the main scaffold protein and least abundant component of the beta-catenin destruction complex, changes in AXIN1 levels affect Wnt signaling output. We show that targeting the Ras-MAPK pathway by MEK1/2 inhibitors induces AXIN1 loss across a panel of CRC cell lines and patient-derived organoids. GSK3B inhibition similarly reduced AXIN1 levels, yet by distinct mechanisms. MEK1/2 causes a reduction of AXIN1 transcript levels, but neither affects protein stability nor post-translational modifications of AXIN1. In contrast, GSK3B inhibition induces rapid AXIN1 degradation. Prevention of AXIN1 loss by co-treatment with tankyrase inhibitors was much stronger for GSK3B than for MEK1/2 inhibition. Using isogenic CRC cell lines and murine intestinal organoids, we show that APC truncations strongly reduce basal AXIN1 levels, but do not alter dynamics of AXIN1 loss upon MEK1/2 inhibition. Polysome profiling and Ribo-Seq revealed that MEK1/2 inhibition reduces global protein synthesis via an mTOR dependent pathway. This translational repression is sufficient to cause significant AXIN1 loss, as treatment with mTOR inhibitors phenocopies the effect of MEK1/2 inhibitors. Our study demonstrates that AXIN1 protein homeostasis is critically controlled by Ras-MAPK signaling at the level of protein synthesis, and that MEK1/2 inhibitors cause AXIN1 loss by translational repression.2026/06/03GSE312194GSM9340203GSM9340204GSM9340201GSM9340202GSM9340188GSM9340189GSM9340200GSM9340209GSM9340207GSM9340208GSM9340205GSM9340206GSM9340195GSM9340196GSM9340193GSM9340194GSM9340191GSM9340192GSM9340190GSM9340214GSM9340212GSM9340213GSM9340210GSM9340199GSM9340211GSM9340197GSM934019824676312194Homo sapiens[42204589]