In this study, we deciphered cellular mechanisms underlying AXIN1 loss by MEK1/2 inhibition in colorectal cancer (CRC). We observed that both MEK1/2 and GSK3B inhibitors strongly reduce AXIN1 levels across multiple CRC models. Inhibition of MEK1/2, but not GSK3B, causes a reduction of AXIN1 transcript levels. While GSK3B inhibition results in rapid protein degradation of AXIN1, targeting of MEK1/2 alters neither protein stability nor post-translational modifications of AXIN1. Instead, MEK1/2 inhibition represses global translation via an mTOR dependent mechanism, which is sufficient to cause AXIN1 loss. Concordantly, mTOR inhibitors phenocopy the effect of MEK1/2 inhibitors on AXIN1 levels. Our study demonstrates that AXIN1 protein homeostasis is critically controlled by Ras-MAPK signaling at the level of protein synthesis, and that its perturbation by MEK1/2 inhibitors result in AXIN1 loss.