Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA342666 | ENA |
REPOSITORIES: ENA
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Project description:Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC). Despite the good initial responses, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), activation of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve and paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced the potency of BV6, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance
2017-01-26 | GSE86839 | GEO
Project description:De novo purine synthesis is required to promote tumor growth; however, its role in therapy resistance remains elusive. Here, through a dynamic BH3-priming based CRISPR-Cas9 screen, we found that deletion of ADSS2, which encodes for an enzyme functioning in de novo AMP synthesis, re-sensitizes drug resistant acute myeloid leukemia (AML) cells to BH3 mimetics. Single-cell sequencing and metabolomics analyses reveal that high ADSS2 activity in leukemia samples including those with TP53 aberrations inversely correlates with venetoclax responsiveness. Further, we developed anADSS2 antagonist, exhibiting synergism with BH3 mimetics in preclinical AML models. Mechanistically, sensitization to BH3 mimetics mediated by ADSS targeting was associated with downregulated AMPK activity, which governs mitochondrial homeostasis. AMPK activity in resistant cells promotes mitophagy to eliminate damaged mitochondria upon BH3 mimetics treatment. These data demonstrate that AMP synthesis governs venetoclax resistance, and that combining ADSS targeting with BH3 mimetic treatment could represent a promising approach against AML.
2025-11-21 | GSE280009 | GEO
Project description:De novo purine synthesis is required to promote tumor growth; however, its role in therapy resistance remains elusive. Here, through a dynamic BH3-priming based CRISPR-Cas9 screen, we found that deletion of ADSS2, which encodes for an enzyme functioning in de novo AMP synthesis, re-sensitizes drug resistant acute myeloid leukemia (AML) cells to BH3 mimetics. Single-cell sequencing and metabolomics analyses reveal that high ADSS2 activity in leukemia samples including those with TP53 aberrations inversely correlates with venetoclax responsiveness. Further, we developed anADSS2 antagonist, exhibiting synergism with BH3 mimetics in preclinical AML models. Mechanistically, sensitization to BH3 mimetics mediated by ADSS targeting was associated with downregulated AMPK activity, which governs mitochondrial homeostasis. AMPK activity in resistant cells promotes mitophagy to eliminate damaged mitochondria upon BH3 mimetics treatment. These data demonstrate that AMP synthesis governs venetoclax resistance, and that combining ADSS targeting with BH3 mimetic treatment could represent a promising approach against AML.
2025-11-21 | GSE280054 | GEO
Project description:BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL1 are in clinical trials. Yet, drug resistance eventually ensues, highlighting the urgency to understand the underlying mechanisms. Our genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy regulators sensitizes AML to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), a GTPase that controls mitochondrial dynamics and the degradation of damaged mitochondria through mitophagy. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. MFN2 inactivation, using a novel small molecule inhibitor, and pharmacologic inhibition of mitophagy synergizes with BH3 mimetics. Overall, targeting of mitophagy along with BCL2-family members is a promising strategy to overcome drug resistance in AML.
2023-07-10 | GSE182401 | GEO
Project description:Small-molecule Smac mimetics target inhibitor of apoptosis (IAP) proteins to induce TNFα-dependent apoptosis in cancer cells and several Smac mimetics have been advanced into clinical development as a new class of anticancer drugs. However, preclinical studies have shown that only a small subset of cancer cell lines are sensitive to Smac mimetics used as single agents and these cell lines are at risk of developing drug resistance to Smac mimetics. Thus, it is important to understand the molecular mechanisms underlying intrinsic and acquired resistance of cancer cells to Smac mimetics in order to develop effective therapeutic strategies to overcome or prevent Smac mimetic resistance. We established Smac mimetic resistant sublines derived from MDA-MB-231 breast cancer cells, which exhibit exquisite sensitivity to the Smac mimetic SM-164, and used microarrays to detail the global programme of gene expression underlying SM-164 resistance in MDA-MB-231 cells and identified differentially expressed genes in SM-164-resistant and -sensitive MDA-MB-231 cells. SCID mice with MDA-MB-231 xenograft tumors were treated with 5 mg/kg of SM-164 intravenously for 5 days/week for 2 weeks. SM-164-regressed MDA-MB-231 tumors regrew after treatment ended. Tumor cells from these regrown MDA-MB-231 tumors were isolated and total RNAs were prepared for microarray analysis.
2012-03-01 | E-GEOD-33827 | biostudies-arrayexpress
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:A fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patient-derived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFalpha exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting.
2019-11-21 | GSE140489 | GEO
Project description:Small-molecule Smac mimetics target inhibitor of apoptosis (IAP) proteins to induce TNFα-dependent apoptosis in cancer cells and several Smac mimetics have been advanced into clinical development as a new class of anticancer drugs. However, preclinical studies have shown that only a small subset of cancer cell lines are sensitive to Smac mimetics used as single agents and these cell lines are at risk of developing drug resistance to Smac mimetics. Thus, it is important to understand the molecular mechanisms underlying intrinsic and acquired resistance of cancer cells to Smac mimetics in order to develop effective therapeutic strategies to overcome or prevent Smac mimetic resistance. We established Smac mimetic resistant sublines derived from MDA-MB-231 breast cancer cells, which exhibit exquisite sensitivity to the Smac mimetic SM-164, and used microarrays to detail the global programme of gene expression underlying SM-164 resistance in MDA-MB-231 cells and identified differentially expressed genes in SM-164-resistant and -sensitive MDA-MB-231 cells.
2012-03-01 | GSE33827 | GEO
Project description:Macrophages engulf apoptotic bodies and cellular debris as part of homeostasis, but they can also phagocytosis live cells such as aged red blood cells. Pharmacologic reprogramming with the SMAC mimetic LCL-161 in combination with T cell-derived cytokines can induce macrophages to phagocytosis live cancer cells in mouse models. Here we extend these findings to encompass a wide range of monovalent and bivalent SMAC mimetic compounds, demonstrating that live cell phagocytosis is a class effect of these agents. We demonstrate robust phagocytosis of live pancreatic and breast cancer cells by primary human macrophages across a range of healthy donors. Unlike mouse macrophages where combination of SMAC mimetics with lymphotoxin enhanced phagocytosis, human macrophages were more efficiently polarized to phagocytose live cells by the combination of SMAC mimetics and IFNg. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNFa production.
2024-11-30 | GSE282835 | GEO
Project description:The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3-mimetics can induce apoptosis. To identify pathways that can regulate sensitivity to BCL-XL inhibition, we screened a compound library for synergy with low dose BCL-XL inhibitor A-1155463 and reveal that FGFR4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.
2021-12-22 | GSE159504 | GEO