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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239683 | GEO | 2024/07/29

REPOSITORIES: GEO

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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

Project description:In colorectal cancer (CRC), WNT/β-catenin signaling is aberrantly activated mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress WNT/β-catenin signaling, are under pre-clinical and clinical trials, while their resistance mechanisms remain unclear. In this study, we established tankyrase inhibitor-resistant CRC cells, JC73-RK100, from APC-mutated patient-derived CRC cells. JC73-RK100 cells and several CRC cells were sensitive to tankyrase inhibitors at low concentrations but were resistant at high concentrations (i.e., bell-shaped dose response: BSDR). Mechanistically, tankyrase inhibitors at high concentrations promoted BRD3/4-dependent E2F target gene transcription and over-activated cell cycle progression in the BSDR cells. BET inhibitors canceled the bell-shaped dose response to tankyrase inhibitors. Taken together, these observations suggest that combination of tankyrase and BET inhibitors would be a useful therapeutic approach to overcome a subset of resistance to tankyrase inhibitors.

2024-07-29 | GSE239681 | GEO

BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

2024-07-29 | GSE239680 | GEO

BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

Project description:BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer

| PRJNA1000553 | ENA

BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

Project description:BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

| PRJNA1000550 | ENA

BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

Project description:BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

| PRJNA1000562 | ENA

Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress APC-mutated colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived APC-mutated CRC cells (JC21 and JC475) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.

2024-01-17 | GSE232209 | GEO

Distinct Colorectal Cancer-Associated APC Mutations Dictate Response to Tankyrase Inhibition.

Project description:The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the mutation cluster region physically engage the destruction complex and suppress the WNT transcriptional program, while APC variants with early truncations (e.g., Apc Min) show limited interaction with AXIN1 and ?-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/?-catenin signaling, but that APC genotype is a crucial determinant of this response. SIGNIFICANCE: This study reveals how subtle changes to the mutations in a critical colorectal tumor suppressor, APC, influence the cellular response to a targeted therapy. It underscores how investigating the specific genetic alterations that occur in human cancer can identify important biological mechanisms of drug response and resistance.This article is highlighted in the In This Issue feature, p. 1325.

| S-EPMC6774804 | biostudies-literature

Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

| PRJNA971219 | ENA

The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.

Project description:Purpose: The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer.Experimental Design: Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches.Results: BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts.Conclusions: Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer. Clin Cancer Res; 23(8); 2027-37. ©2016 AACR.

| S-EPMC5368030 | biostudies-literature

3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors.

Project description:Aberrant activation of the Wnt signalling pathway is required for tumour initiation and survival in the majority of colorectal cancers. The development of inhibitors of Wnt signalling has been the focus of multiple drug discovery programs targeting colorectal cancer and other malignancies associated with aberrant pathway activation. However, progression of new clinical entities targeting the Wnt pathway has been slow. One challenge lies with the limited predictive power of 2D cancer cell lines because they fail to fully recapitulate intratumoural phenotypic heterogeneity. In particular, the relationship between 2D cancer cell biology and cancer stem cell function is poorly understood. By contrast, 3D tumour organoids provide a platform in which complex cell-cell interactions can be studied. However, complex 3D models provide a challenging platform for the quantitative analysis of drug responses of therapies that have differential effects on tumour cell subpopulations. Here, we generated tumour organoids from colorectal cancer patients and tested their responses to inhibitors of Tankyrase (TNKSi) which are known to modulate Wnt signalling. Using compounds with 3 orders of magnitude difference in cellular mechanistic potency together with image-based assays, we demonstrate that morphometric analyses can capture subtle alterations in organoid responses to Wnt inhibitors that are consistent with activity against a cancer stem cell subpopulation. Overall our study highlights the value of phenotypic readouts as a quantitative method to asses drug-induced effects in a relevant preclinical model.

| S-EPMC7433887 | biostudies-literature

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