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MEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RNASeq_SW480]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312195 | GEO | 2026/06/03

REPOSITORIES: GEO

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MEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RNASeq_HCT116]

Project description: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.

2026-06-03 | GSE312194 | GEO

MEK inhibition induces AXIN1 loss in colorectal cancer by mTOR associated suppression of protein synthesis [RiboSeq_HCT116]

2026-06-03 | GSE312196 | GEO

Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Illumina]

Project description:Resistance to Ras pathway inhibition is a major challenge in the treatment of colorectal cancer (CRC), but the underlying mechanisms are incompletely understood. Here we performed large-scale small molecule screens in CRC and identified inhibitors of MEK1/2 as potent activators of Wnt/beta-catenin signalling. Targeting MEK increased Wnt activity in different CRC cell lines and in the murine intestine in vivo. The MEK-induced Wnt response was strongly enhanced by truncating mutations in APC and proteomic experiments identified that AXIN1 levels are depleted upon MEK inhibition. We generated patient-derived colon cancer organoids and showed that a clinically approved MEK inhibitor leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stem cells and cancer relapse. This reprogramming was reverted by co-treatment with Wnt inhibitors. Our study demonstrates that MEK inhibition affects cellular plasticity and induces an intestinal stem cell program which constitutes a novel mechanism of drug resistance.

2018-05-08 | GSE114059 | GEO

Small molecule inhibition of MEK activates Wnt signalling and leads to reprogramming of colon cancer stem cells [Affymetrix]

2018-05-08 | GSE114060 | GEO

Transcriptomic changes in response to inducible CTNNB1 activation in murine B-ALL cells

Project description:As part of canonical WNT signaling, TCF7/β-catenin-complexes promote MYC-dependent proliferation. Compared to solid tumors, we found that B-cell acute lymphoblastic leukemia (B-ALL) cells, express β-catenin protein at 80- to 200-fold lower levels and critically depend on its efficient degradation: β-catenin protein was constitutively phosphorylated by GSK3B and poised for proteasomal degradation. Lesions of the β-catenin-protein degradation machinery are common oncogenic drivers, however, B-ALL cells lacked these mutations and critically depend on unencumbered β-catenin-protein degradation. Instead of TCF7/β-catenin-complexes to activate MYC, β-catenin paired with B-lymphoid Ikaros factors, resulting in MYC-repression and acute cell death. To leverage β-catenin-protein degradation as previously unrecognized vulnerability in B-ALL, we validated GSK3B-inhibition in patient-derived xenograft models in vivo. CRISPR/Cas9 chemogenomic screens confirmed β-catenin protein degradation as central mechanistic target of established GSK3B-inhibitors. Based on favorable safety profiles in clinical trials, our results provide a rationale for repurposing existing GSK3B-inhibitors for patients with refractory B-cell malignancies.

2025-09-22 | GSE305472 | GEO

Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory circuits During Response to MAPK Inhibition in BRAF-mutant colorectal cancer

Project description:Background: Aberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC). BRAFV600E-mutated metastatic CRC may be a unique subtype, exhibiting a strong epigenetic phenotype. Interestingly, bromodomain 2, a reader protein for H3K27ac-marked enhancers, was found to be synthetically lethal in CRC with BRAF + EGFR inhibition. Design: We evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive profiling of transcriptomic and chromatin dynamics upon BET inhibitor combination treatment. Results: The combination of BET and standard MAPK inhibitors has demonstrated improved efficacy against BRAFV600E CRC and selective improvements against RAS-mutant CRC in vivo. We showed that BET + MAPK inhibition induced a profound downregulation of the MAPK signaling pathway compared to MAPK inhibition alone. The loss of activation signal on enhancers, as determined by H3K27ac, led to dysregulation of core-regulatory circuitries of CRC, especially loss of the auto-regulatory mechanism of the MAPK downstream E26 transformation–specific transcription factor family. Single nucleus multiome (RNA + ATAC) sequencing further distinguished differential transcriptomic and chromatin dynamics at cell type levels. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream transcription factors. On the other hand, dedifferentiated cell populations were abundant after MAPK or combination inhibition, suggesting therapy-induced cell state switching and adaptation. Conclusion: We are evaluating BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic CRC. ClinicalTrial.gov identifier: NCT06102902.

2026-04-24 | GSE280280 | GEO

Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory circuits During Response to MAPK Inhibition in BRAF-mutant colorectal cancer.

2026-04-24 | GSE280266 | GEO

Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition

Project description:The heat-shock protein 90 (HSP90) is a promising target in cancer therapy, but its inhibitors' clinical trial failures are partly due to a compensatory heat-shock response (HSR) mediated by heat-shock factor 1 (HSF1). We previously showed that wildtype p53 reduces HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we explore if simultaneous p53 activation or cell cycle inhibition can disrupt the HSF1-HSR axis and enhance HSP90 inhibitors' efficiency. mRNA sequencing was performed on HCT116 cells treated for 24 hours with DMSO, 50 nM Ganetespib, 1 µM RG-7388, or their combination. We found that the p53 activator Idasanutlin suppresses HSF1-HSR activity in HSP90 inhibitor-based therapies, synergistically reducing cell viability and accelerating cell death in p53-proficient colorectal cancer (CRC) cells and organoids. Combination therapy upregulates p53 pathways, apoptosis, and inflammation. In a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and alters immune cell composition. CDK4/6 inhibition under HSP90 inhibition mimics HSR repression in p53-proficient CRC cells. In p53-deficient CRC cells and p53-mutated organoids, combined HSP90 and CDK4/6 inhibition suppresses HSF1-HSR and reduces cancer growth, offering a p53-independent strategy for CRC treatment. In conclusion, we present new options to improve HSP90-based therapies for enhanced CRC treatment.

2025-03-28 | E-MTAB-14877 | biostudies-arrayexpress

Effect of PTEN knockout on dabrafenib-trametinib treatment in A375 melanoma cells - replicate 1

Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. RNA sequencing and functional kinome analysis revealed the loss of PTEN led to an induction of FOXD3 and an increase in expression of the FOXD3 target gene, ERBB3/HER3. Inhibition of BRAFand MEK1/2 in PTEN null, BRAFV600E cells dramatically induced expression of ERBB3/HER3 relative to wild type cells. A synergy screen of epigenetic modifiers and kinase inhibitors in combination with inhibitors for mutant BRAF/MEK1/2 identified the pan ERBB/HER inhibitor, neratinib, as reversing the resistance observed in PTEN null, BRAFV600E cells. The findings indicate PTEN null BRAFV600E melanoma becomes dependent on ERBB/HER signaling when treated with clinically approved BRAF and MEK inhibitors. Future studies are warranted to test neratinib reversal of resistance in patient melanomas expressing ERBB3/HER3 in combination with its dimerization partner ERBB2/HER2.

2024-04-23 | PXD033866 | Pride

Breast Cancer Suppressor Role of RUNX1: Estrogen-dependent Regulation of AXIN1 and b-catenin

Project description:The transcription factor RUNX1 exhibits recurrent loss-of-function mutations in estrogen receptor-positive (ER+) breast cancer (BCa). Its knockdown in vitro decreased AXIN1 expression in estrogen-dependent manner. Consistently, RUNX1 and AXIN1 mRNA levels are strongly correlated in ER+, not ER- tumors. RUNX1 occupies AXIN1â??s second intron in living cells, abutting an ERa-binding site. Potentially promoting BCa progression, decreased AXIN1 expression after RUNX1 knockdown associated with upregulation of b-catenin, and this was preventable by AXIN stabilizers. Unlike in colon cancer, however, deregulation of b-catenin in BCa cells affect neither c-Myc, nor CCND1, nor G1/S cell cycle phase transition. Instead, cyclin B1 was decreased and the G2/M checkpoint was compromised as indicated by mitotic slippage in the presence of microtubule disruptors. Thus, combined analysis of the RUNX1 transcriptome, its cistrome, and differential mRNA expression in tumors with wild type versus mutant RUNX1, altogether highlight a role for the RUNX1/AXIN1/b-catenin axis in ER+ BCa. Significance: Three recent exome sequencing studies assigned to RUNX1 a BCa suppressor role. The present study begins to uncover the underlying molecular mechanisms, offers an explanation for the specificity to ER+ tumors, and marks AXIN1 as a therapeutic target for ER+/RUNX1- BCa. Examination of RUNX1 binding in MCF7 cells

2016-02-22 | E-GEOD-65313 | biostudies-arrayexpress

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