Potentiating radiation-induced T1IFN and the anti-tumoral immune response with the ATM inhibitor AZD1390 in pancreatic cancer
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ABSTRACT:
PROVIDER: PRJNA1071152 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27792591_1.fastq.gz | Fastqsanger.gz | |||
| SRR27792591_2.fastq.gz | Fastqsanger.gz | |||
| SRR27792592_1.fastq.gz | Fastqsanger.gz | |||
| SRR27792592_2.fastq.gz | Fastqsanger.gz | |||
| SRR27792593_1.fastq.gz | Fastqsanger.gz |
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Project description:Radiotherapy induces a Type I interferon (TIFIN)-mediated anti-tumoral immune response that we hypothesized could be potentiated by a first-in-class ATM inhibitor leading to enhanced innate immune signaling. T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound AZD0156 on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced anti-tumoral immune responses and sensitized to anti-PD-L1, producing immunogenic memory and durable tumor control. Therapeutic responses were associated with increased CD8+ T cell frequency and effector function. Tumor control was dependent on CD8+ T cells as therapeutic efficacy was blunted in immunodeficient or CD8+ T cell-depleted mice. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN leading to both innate and subsequent adaptive immune response and sensitization of otherwise resistant pancreatic cancer to immunotherapy.
2024-05-08 | GSE254624 | GEO
Project description:As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several potential cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM’s canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM regulates radiation-induced apoptosis. This acute, ATM-dependent apoptosis is a key determinant of long-term animal survival. Our results suggest that inhibition of ATM in these organisms could therefore potentially favor cell survival after radiation without obvious effects on stem cell behavior.
2022-12-25 | GSE190454 | GEO
Project description:Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration, telangiectasias, acute cancer predisposition, and hypersensitivity to ionizing radiation (IR). The gene defective in AT, ATM (for AT-mutated), encodes a protein, pATM that has been found to have IR-inducible kinase activity. Cells from individuals with AT exhibit severely attenuated cell cycle checkpoints in response to gamma radiation exposure. pATM has been hypothesized to act as part of a complex that senses DNA damage, in particular, DNA double strand breaks. We are studying the pATM-dependent gene expression responses to a dose of 1.5 Gy radiation in lymphoblastoid cell lines from multiple individuals with either wild type or mutated ATM. The gene expression analyses were performed on Agilent Human 1A Oligo chips containing approximately 16,000 60mer probes. We identified a set of genes whose gene expression changes are ATM-dependent following exposure to 1.5 Gy IR. This set of genes was tested by real time quantitative PCR analysis.
2013-12-02 | GSE19287 | GEO
Project description:Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration, telangiectasias, acute cancer predisposition, and hypersensitivity to ionizing radiation (IR). The gene defective in AT, ATM (for AT-mutated), encodes a protein, pATM that has been found to have IR-inducible kinase activity. Cells from individuals with AT exhibit severely attenuated cell cycle checkpoints in response to gamma radiation exposure. pATM has been hypothesized to act as part of a complex that senses DNA damage, in particular, DNA double strand breaks. We are studying the pATM-dependent gene expression responses to a dose of 1.5 Gy radiation in lymphoblastoid cell lines from multiple individuals with either wild type or mutated ATM. The gene expression analyses were performed on Agilent Human 1A Oligo chips containing approximately 16,000 60mer probes. We identified a set of genes whose gene expression changes are ATM-dependent following exposure to 1.5 Gy IR. This set of genes was tested by real time quantitative PCR analysis. The study consists of one dose group - 1.5 Gray gamma radiation. Samples were collected 6 hr following irradiation (treated) or mock irradiation (controls) for each culture. Each culture has a treated sample and a control sample. There are cultures from 6 wild-type ATM individuals and cultures from 6 individuals that are ATM-deficient, for a total of 12 cultures. Hybridizations compared RNA extracted from each individual culture's treated sample against its corresponding control sample, and were performed as dye-flip duplicates (1 replicate in each direction). Hybridizations were performed on the Human 1A Oligo Chips using low input, direct labeling at Paradigm Genetics Laboratory. Microarray scanning was performed with the Agilent G2565AA Scanner. Paradigm Standard Operating Procedures were followed for quality analysis, sample labeling, microarray hybridization and washing, scanning, image analysis and initial data analysis.
2013-12-02 | E-GEOD-19287 | biostudies-arrayexpress
Project description:GM0637 cell were pretreated with ATM inhibitor before adding DNA damaging agent neocarzinostatin (NCS), and cells were harvested after 4 hours for the microarray analyses of whole-genome miRNAs. To examine how miRNAs are regulated in the DNA damage response, we assessed the genome-wide mature miRNA expression in GM0637 cells treated with or without ATM inhibitor (ATM-IN)
2012-11-14 | E-GEOD-42248 | biostudies-arrayexpress
Project description:Investigation of ATM-dependent and dose-dependent, or -independent, responses were examined in human lymphoblast cells 6 hr following exposure to either 1 or 5 Gy ionizing radiation. Keywords: cDNA, dual-channel
2006-01-15 | GSE3174 | GEO
Project description:Investigation of ATM-dependent and dose-dependent, or -independent, responses were examined in human lymphoblast cells 6 hr following exposure to either 1 or 5 Gy ionizing radiation. Human lymphoblast cells from "apparently healthy" individuals and individuals with Ataxia telangiectasia were exposed to 1 Gy or 5 Gy ionizing radiation. Gene expression responses 6 hr following IR were examined. Untreated samples were hybridized together with their matched treated samples.
2010-07-01 | E-GEOD-3174 | biostudies-arrayexpress
Project description:Analysis of gene expression changes in galactose-induced cataracts when an Atm inhibitors is added. A total of six samples were analyzed: a sample without induced turbidity (control), three samples in which turbidity was induced by galactose (galactose), and a sample with ATM inhibitor added (KU55933 or AZD0156).
2022-09-24 | GSE194074 | GEO
Project description:Inhibition of the ATM kinase rescues planarian regeneration after lethal radiation
| PRJNA787217 | ENA
Project description:Purpose: Central nervous system (CNS) metastasis has remained a major source of mortality for breast cancer patients. This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated (ATM) inhibitor, as a radiosensitizer for breast cancer CNS metastasis treatment. Experimental Design: Three PDX tumors including 2 HER2+ and 1 triple negative breast cancer (TNBC) harboring TP53 mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. Results: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival 222 days compared to 123 days in controls. Adjuvant administration of AZD1390 had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in in some mice 50-100 days post-treatment in all models. Gene expression analysis comparing these tumors with complete responders demonstrated changes in upregulation of multiple oncogenic proteins, which are potential drivers of tumor growth after treatment. Conclusions: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CNS metastasis to radiation therapy in TP53 mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CNS metastasis.
2023-08-01 | GSE224899 | GEO