Ras‑MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis
Ras‑MAPK inhibition by clinically approved MEK1/2 inhibitors induces AXIN1 loss in colorectal cancer through mTOR‑mediated suppression of global protein synthesis
AXIN1 is a central regulator of many oncogenic pathways in colorectal cancer (CRC). This study demonstrates that targeting the Ras‑MAPK pathway with MEK1/2 inhibitors leads to AXIN1 loss across CRC cell lines and patient‑derived organoids. The loss is not due to decreased protein stability or post‑translational modification but results from repression of global protein synthesis via an mTOR‑dependent mechanism. Co‑treatment with tankyrase inhibitors partially rescues AXIN1 levels, highlighting a cross‑talk between MAPK and Wnt signaling.
The findings reveal a mechanistic basis for the limited efficacy of MEK inhibitors in CRC: loss of AXIN1 activates Wnt signaling, potentially contributing to drug resistance. Understanding this cross‑talk is essential for designing combination therapies that mitigate Wnt‑mediated resistance.
Evidence level: Korai humán adat. Kis vagy feltáró emberi adat.
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