Similar Datasets
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
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 | GSE239680 | GEO
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
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
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
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
Project description:Activation of Wnt/?-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/?-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor-resistant cell line, 320-IWR, from Wnt/?-catenin-dependent CRC COLO-320DM cells. 320-IWR cells exhibited resistance to tankyrase inhibitors, IWR-1 and G007-LK, but remained sensitive to a PARP-1/2 inhibitor, olaparib, and several anti-CRC agents. In 320-IWR cells, nuclear localization of active ?-catenin was decreased and expression of ?-catenin target genes was constitutively repressed, suggesting that these cells repressed the Wnt/?-catenin signaling and were dependent on alternative proliferation pathways. 320-IWR cells exhibited upregulated mTOR signaling and were more sensitive to mTOR inhibition than the parental cells. Importantly, mTOR inhibition reversed resistance to tankyrase inhibitors and potentiated their anti-proliferative effects in 320-IWR cells as well as in CRC cell lines in which the mTOR pathway was intrinsically activated. These results indicate that mTOR signaling confers resistance to tankyrase inhibitors in CRC cells and suggest that the combination of tankyrase and mTOR inhibitors would be a useful therapeutic approach for a subset of CRCs.
| S-EPMC5564614 | biostudies-literature
Project description:Simple Summary Hyperactivation of the canonical Wnt and inactivation of the Hippo pathway are well-known genetic backgrounds for familial adenomatosis polyposis (FAP) and colorectal cancer (CRC), although the reciprocal regulation between those pathways is not yet clear. In this study, we found that Axin2, a bona fide downstream target of canonical Wnt, activates the Hippo pathway in APC-mutated CRC, limiting the therapeutic potential of niclosamide on advanced CRC through the inactivation of the Hippo pathway. To overcome the limitation, we combined niclosamide with AMPK activator metformin to activate Hippo and found that this combination synergistically suppressed canonical Wnt and activated Hippo in APC-mutated CRC. Using patient-derived cancer organoid and an APC-MIN mice model, we found the combinatory approach to be effective for APC-mutated CRC. Our results provide not only the reciprocal link between Wnt and Hippo in APC-mutated CRC, but they also provide an effective therapeutic approach with clinically available drugs for FAP and CRC patients. Abstract The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.
| S-EPMC8308039 | biostudies-literature
Project description:We report that OTX015 upregulates BCL6 in KRAS-mutant NSCLC cells. Considering that both BCL6 and BET proteins regulate target genes by affecting transcription, we performed an RNA-seq experiment to identify downstream genes which response to OTX015. Retinal mRNA profiles of A549 cells treated with DMSO (0.1% for 6 hr) and OTX015 (1 μM for 6 hr) were generated by deep sequencing, in triplicate, using the SOLiD v4 sequencing platform. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows-Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. qRT-PCR validation was performed using TaqMan and SYBR Green assays.
2019-08-15 | GSE118645 | GEO
Project description:The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors; however, inherent resistance remains a major challenge in the clinic. Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non-small-cell lung cancer (NSCLC). We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC.
| S-EPMC7773368 | biostudies-literature