PhD Scientific Days 2026

Molecular Medicine 3.

MEK1/2 inhibition induces persistent growth arrest via Wnt hyperactivation, defining a chemoresistance mechanism in EGFR/MAPK wild-type colorectal cancer

Name of the presenter

Orosz, Adrián

Institute/workplace of the presenter

Institute of Genetics, Cell and Immunobiology, Molecular Cancer Research Group, Semmelweis University, Budapest, Hungary

Authors

Adrián Orosz Dr.¹
1: Institute of Genetics, Cell and Immunobiology, Molecular Cancer Research Group, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction
Colorectal cancer (CRC) progression is driven by interconnected signaling networks that regulate proliferation and cellular plasticity. Despite the fact that MAPK pathway activity is essential for CRC cell growth and is also a clinically relevant therapeutic target, the consequences of its inhibition in KRAS wild-type CRC remain poorly understood.
Aims
We aimed to define the cellular and molecular responses to MAPK pathway inhibition, with a focus on Wnt signaling in a 3D organoid system that provenly recapitulates the in vivo intra-tumoral heterogeneity.
Methods
Patient-derived organoids (PDOs) from KRAS wild-type CRC were cultured in 3D matrix and treated with the MEK inhibitor trametinib (MEKi). Phenotypic changes were assessed by flow cytometry, light and confocal microscopy, while transcriptional alterations were analyzed by RNA profiling and RT-qPCR. Wnt pathway activation was functionally tested using GSK inhibition (GSKi).
Results
MEKi induced a stable growth arrest characterized by reduced proliferation and diminished organoid-forming capacity, persisting even after drug withdrawal. This state was not accompanied by increased DNA damage or senescence. Transcriptomic analysis revealed a distinct reprogramming marked by robust upregulation of canonical Wnt target genes, including AXIN2 and LGR5, together with activation of stem cell-associated programs such as PROX1. Notably, this Wnt hyperactivation coincided with features of epithelial plasticity, including partial epithelial–mesenchymal transition (EMT)-like transcriptional changes and loss of epithelial identity. Pharmacological activation of Wnt signaling phenocopied the partial EMT and anti-proliferative effects of MEKi. In parallel, both MEKi and GSKi reduced mTOR activity, as indicated by decreased phospho-S6 levels, and enriched for a slow-cycling cell population, supporting a causal role for Wnt hyperactivation in growth suppression.
Conclusion
MEK inhibition in KRAS wild-type CRC enforces a persistent, low-proliferative state driven by Wnt pathway hyperactivation coupled with low-growth and partial EMT features, identifying Wnt hyperactivation-driven growth arrest as a key adaptive response to MEK inhibition and a potential therapeutic target for combination therapies.
Funding
TKP2021-EGA-24, Advanced K152735 (NRDI Office, HUN). Ethical approval: TUKEB 2015, 51323-4/2015/EKU