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ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma

ABSTRACT: Metastatic clear cell renal cell carcinomas (ccRCC) are resistant to DNA damaging chemotherapies, limiting therapeutic options for patients whose tumours are resistant to tyrosine kinase inhibitors and/or immune checkpoint therapies. Here we show that mouse and human ccRCC are frequently characterised by high levels of endogenous DNA damage and that cultured ccRCC cells exhibit intact cellular responses to chemotherapy-induced DNA damage. We identify that pharmacological inhibition of the DNA damage sensing kinase ATR with the orally administered, potent and selective drug M4344 induces anti-proliferative effects in ccRCC cells due to replication stress and the accumulation of DNA damage in S phase. In some cells, DNA damage persists into subsequent G2/M and G1 phases, leading to the frequent accumulation of micronuclei. Daily single agent treatment with M4344 inhibited the growth of ccRCC xenograft tumours. M4344 synergises with chemotherapeutic drugs including cisplatin and carboplatin and the PARP inhibitor olaparib in mouse and human ccRCC cells. Weekly M4344 plus cisplatin treatment showed in vivo therapeutic synergy in ccRCC xenografts and was efficacious in an autochthonous mouse ccRCC model. These studies identify ATR inhibition as a potential novel therapeutic option for ccRCC.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE211466 | GEO | 2022/11/23

REPOSITORIES: GEO

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RNAseq analysis of tumours from GEMMS animals to determine the effect of different aPDL1 combinations on lung tumours in situ

Project description:This study aims to identify combination treatments capable of inducing improved IO responses in lung tumours and thus, help guide decisions on the next combination arms for the HUDSON trial (post-IO). For that purpose, a lung tumour GEMM model was treated with either vehicle, PD-L1, ATR, ATR/PD-L1; Cisplatin/PD-L1/Ctla4 or VEGFR/PD-L1 and tumours collected for transcriptional profiling.

2024-01-29 | E-MTAB-13704 | biostudies-arrayexpress

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

Project description:High-risk neuroblastoma (NB) often involves amplification of the neural MYC (MYCN) oncogene as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes such as MYCN and ALK result in increased replication stress in cancer cells, offering one such therapeutically exploitable option. Here, we followed up on earlier phosphoproteomic analyses that identified ATR activity in ALK-driven NB cell lines. We tested several ATR inhibitors, identifying BAY 1895344 as the most potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterized the response of NB cells and tumours to ATR inhibition, identifying key components of the DNA damage response (DDR) as well as ATRX, MYCN, E2F and DCK among other ATR targets in NB cells. ATR inhibition with BAY 1895344 also produced robust responses in mouse NB models. Remarkably, a 2 week protocol combining ATR and ALK inhibition led to complete regression of NB tumours in two independent NB genetically modified mouse tumour models. These results suggest that NB patients, particularly in high-risk groups with oncogene induced replication stress, may benefit from inhibition of ATR as therapeutic intervention.

2021-11-02 | PXD027187 | Pride

Genome-wide fork-collapse sites in MEFs from ATR inhibition

Project description:Transient obstruction of DNA polymerase progression activates the ATR checkpoint kinase, which suppresses fork breakage, strand resection, and RPA accumulation. Herein, we use RPA ChIP-Seq to identify replication-problematic loci (RPLs) across the mammalian genome from ATR inhibition.

2018-10-04 | GSE100790 | GEO

Quantitative phosphoproteomics to unravel the cellular response to chemical stressors with different modes of action

Project description:Cells activate various stress response pathways when exposed to chemicals that can damage cellular macromolecules and organelles. Whether different chemical stressors activate common and/or stressor-specific pathways and to what extent is largely unclear. Here, we used quantitative phosphoproteomics to compare the phosphorylation signaling cascades induced by four stressors with different modes of action: the DNA damaging agent: cisplatin (CDDP), the topoisomerase II inhibitor: etoposide (ETO), the pro-oxidant: diethyl maleate (DEM) and the immunosuppressant: cyclosporine A (CsA). We show that equitoxic doses of these stressors induce distinctive and complex phosphorylation signaling cascades. Our results reveal stressor-specific kinase motifs and pathways. CDDP activates the DNA damage response (DDR) predominantly through the replication-stress related Atr kinase, whereas ETO triggers the DDR through Atr as well as the DNA double stranded break associated Atm kinase. CsA shares with ETO, a strong activation of CK2 kinase and significant Atm phosphorylation but lacks prominent activation of the DDR. Congruent with their known modes of action, CsA-mediated signaling is related to down-regulation of pathways that control hematopoietic differentiation and immunity whereas oxidative stress is the most prominent initiator of DEM-modulated stress signaling. This study presents an unprecedented molecular insight into the activated phosphorylation signaling cascades after various types of stressors.

2020-03-23 | PXD012559 | Pride

Genome-wide fork-collapse sites in MEFs from ATR inhibition [mouse]

Project description:Transient obstruction of DNA polymerase progression activates the ATR checkpoint kinase, which suppresses fork breakage, strand resection, and RPA accumulation. Herein, we use a developed DNA break-detection assay, BrITL, to identify replication-problematic loci (RPLs) that become processed into persistent double-strand breaks across the mammalian genome from ATR inhibition.

2018-10-04 | GSE115624 | GEO

Genome-wide fork-collapse sites in MDA-MB-231 cells from ATR inhibition [human]

Project description:Transient obstruction of DNA polymerase progression activates the ATR checkpoint kinase, which suppresses fork breakage, strand resection, and RPA accumulation. Herein, we use a developed DNA break-detection assay, BrITL, to identify replication-problematic loci that become processed into persistent double-strand breaks across the human genome from ATR inhibition.

2018-10-04 | GSE115623 | GEO

Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

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2012-03-22 | E-GEOD-28330 | biostudies-arrayexpress

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2006-10-30 | E-MEXP-780 | biostudies-arrayexpress

Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition

Project description:Excessive genomic instability coupled with abnormalities in DNA repair pathways induce high levels of “replication stress” when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention toward targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1 and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective inhibitor of ATR kinase elimusertib (BAY 1895344), has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated-CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity.

2022-11-09 | GSE217579 | GEO

ATR Mutations Promote the Growth of Melenama Tumor by Modulating the Immune Microenvironment [tumor]

Project description:Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet these tumors are still able to suppress the immune response in order to facilitate their continued growth. In this study, we identify subsets of human melanoma tumors that have partial loss of function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T-cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a novel mechanism by which melanoma cells modulate the immune microenvironment to allow continued tumor growth.

2017-01-31 | GSE94264 | GEO

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