Homo sapiens
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PROVIDER: PRJNA205300 | ENA |
REPOSITORIES: ENA
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Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Experiment Overall Design: Naive cell lines were isolated in duplicate or triplicate (only a single for H69AR) to determine RNA expression pattern.
2008-06-19 | E-GEOD-10841 | biostudies-arrayexpress
Project description:BH3 mimetics are increasingly used as anti-cancer therapeutics either alone or in conjunction with other chemotherapies. However, mounting evidence has also demonstrated that BH3 mimetics induce varied amounts of cell death in healthy immune populations. In order to maximize their clinical potential, it is essential to understand how BH3 mimetics affect discrete immune populations and to determine how BH3 mimetic pressure causes immune system adaptation. Here we focus on the BCL-2 specific inhibitor venetoclax (ABT-199) and its effects following short-term and long-term BCL-2 blockade on T cell subsets. Seven day "short-term” ex vivo and in vivo BCL-2 inhibition led to divergent cell death sensitivity patterns in CD8+ T cells, CD4+ T cells, and Tregs resulting in shifting of global T cell populations towards a more memory T cell state with increased expression of BCL-2, BCL-XL, and MCL-1. However, twenty-eight day “long-term” BCL-2 blockade during T cell engraftment following bone marrow transplantation did not lead to changes in the global T cell landscape. Despite the lack of changes in T cell proportions, animals treated with venetoclax developed CD8+ and CD4+ T cells with high levels of BCL-2 and were more resistant to apoptotic stimuli. Further, we demonstrate through RNA profiling that T cells adapt while under BCL-2 blockade post-transplant and develop a more activated genotype. Taken together, these data emphasize the importance of evaluating how BH3 mimetics affect the immune system in different treatment modalities and disease contexts and suggest that venetoclax should be further explored as an immunomodulatory compound.
2021-11-01 | GSE164483 | GEO
Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Keywords: cell line comparison
2008-05-01 | GSE10841 | GEO
Project description:Nasopharyngeal carcinoma (NPC) is among a small number of solid tumors that are caused by the Epstein-Barr virus (EBV). Recently, BH3 mimetics, a novel class of drugs that inhibit pro-survival proteins of the BCL-2 family, have demonstrated clinical anti-cancer efficacy in hematological malignancies and are being investigated for use in solid tumors. There is known dysregulation of pro-survival pathways, particularly, the intrinsic apoptotic pathway during EBV infection of B cells suggesting NPC may be driven by the same pathways, and thus sensitive to BH3 inhibition. Using immunohistochemistry, we examined the expression of BCL-2 family of proteins (BCL2, MCL1 and BCLxL) in 174 NPC from patients treated with curative intent as well as five NPC cell lines. We subsequently evaluated the anti-tumor efficacy of three BH3 mimetics (ABT-199, ABT-737 and S63845) in NPC cells alone or in combination with cisplatin, a commonly used cytotoxic agent in NPC treatment. BCL-2 was highly expressed in NPC tumors and cells. Despite this, BCL2 inhibition, or BH3 monotherapy was not effective. However, marked sensitivity was observed with the combination S63845 (targeting MCL-1) and cisplatin in NPC43, which had high expression of MCL-1. This combination resulted in upregulation of pro-apoptotic tBID suggesting a priming role of cisplatin and apoptotic potentiation through MCL-1 inhibition. Flow cytometry studies and RNA sequencing of NPC43 cells treated with the combination of cisplatin with S63845 and untreated cells showed death by apoptosis and upregulation in stress response and DNA damage pathways. Our study suggests that combining BH3 mimetics with cisplatin could be an effective treatment strategy for NPC and warrants further investigation
2024-10-01 | GSE235574 | GEO
Project description:Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 (BH3) mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with treated cells compared with cells from untreated mice, with a reduction of bone marrow (BM) blasts, LSK and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by Tc-99m-labeled Annexin V single photon emission computed tomography (SPECT) and ex vivo by Annexin V/7AAD flow cytometry, TUNEL, caspase 3 cleavage and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type AKT, ERK1/2 and MEK patterns in spleen cells after treatment, which show reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells. NRASD12/BCL-2 double transgenic mice were analysed by enriching for primitive Sca1+ cells from splenocytes from untreated and ABT-737 treated mice. RNA was extracted analysed for gene expression profiles using exon specific arrays.
2013-11-06 | E-GEOD-48601 | biostudies-arrayexpress
Project description:GSK3alpha has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3alpha over GSK3beta and other kinases. We have previously shown in lung cancer cells that GSK3alpha and to a lesser extent GSK3beta are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of beta-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced beta-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3alpha/beta inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML.
2019-01-29 | PXD010217 | Pride
Project description:Intrinsic apoptosis is principally regulated by the BCL-2 family of proteins, but some non-BCL-2 proteins also serve as important regulators. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in multiple BAX-deficient cell lines conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an active conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins. This study identifies a mechanism by which MARCHF5 regulates apoptotic cell death and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.
2022-09-25 | PXD030246 | Pride
Project description:Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo. Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241
2013-04-03 | E-GEOD-36938 | biostudies-arrayexpress
Project description:TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
2024-04-25 | GSE261373 | GEO
Project description:Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions, yet the potential for targeting such senescent cells for improved therapy remains largely unknown. Here, we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs represented different previously-defined CAF subtypes. Senescent CAFs isolated from mouse and humans expressed elevated levels of immunoregulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
2024-06-24 | PXD053144 | Pride