Ras-MAPK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis.
Summary
This study demonstrates that MEK1/2 inhibitors, targeting the Ras-MAPK pathway, induce AXIN1 protein loss in colorectal cancer cell lines and patient-derived organoids. Unlike GSK3 inhibitors, this loss is not attributed to altered AXIN1 protein stability or post-translational modifications, nor to a significant reduction in its transcript levels. Analyses revealed that MEK1/2 inhibitors reduce global protein synthesis via an mTOR-associated pathway, an effect sufficient to cause AXIN1 loss. Co-treatment with tankyrase inhibitors was shown to partially prevent this AXIN1 reduction.
Analysis
This research is significant as it uncovers an unexpected mechanism by which MEK inhibitors, targeted therapies used in oncology, impact AXIN1 protein homeostasis. AXIN1 is a crucial regulator of the Wnt pathway, which is frequently dysregulated in colorectal cancer. Understanding that Ras-MAPK inhibition can modulate Wnt signaling through protein synthesis offers new avenues for combination therapeutic strategies, potentially by sensitizing cells to treatments or explaining certain resistances. This highlights the importance of investigating the pleiotropic effects of targeted therapies beyond their primary targets.