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ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma

ABSTRACT: ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma

PROVIDER: PRJNA870454 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21105951_1.fastq.gz	Fastqsanger.gz
	SRR21105951_2.fastq.gz	Fastqsanger.gz
	SRR21105952_1.fastq.gz	Fastqsanger.gz
	SRR21105952_2.fastq.gz	Fastqsanger.gz
	SRR21105953_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma

Project description: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.

2022-11-23 | GSE211466 | GEO

ATR represents a therapeutic vulnerability in clear cell renal cell carcinoma.

Project description: Not available

| S-EPMC9869969 | biostudies-literature

KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant NSCLC

Project description:KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of tumors associated with resistance to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA-damage response (DDR)-based therapies, the impact of KEAP1 alterations remains unknown. Here we demonstrate that KEAP1/NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi) particularly in the setting of increased replication stress associated with LKB1 loss. ATRis show enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient NSCLC models and synergy combined with gemcitabine. ATRi also enhances antitumor immunity and helps mitigate the immunosuppressed phenotype of LKB1 and/or KEAP1-deficient tumors. Finally, in the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1/NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as useful biomarkers for predicting response to ATRi combination regimens.

2025-06-15 | E-MTAB-15235 | biostudies-arrayexpress

SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma

Project description:Immune checkpoint blockade (ICB) demonstrates durable clinical benefit only in a minority of renal cell carcinoma (RCC) patients. Identifying molecular features that determine response and developing approaches to enhance the response remain an urgent clinical need. Here we found that, in multiple RCC cell lines, targeting the ATR-CHK1 axis with pharmacological inhibitors increased cytosolic DNA accumulation, activated the cGAS-IRF3-dependent cytosolic DNA sensing pathway, and resulted in the inflammatory cytokine expression. SETD2 mutated RCC cell lines or tumor samples were associated with preferential ATR-CHK1 activation over ATM-CHK2 activation. SETD2 knockdown promoted the cytosolic DNA sensing pathway and conferred greater sensitivity in response to ATR-CHK1 inhibition. In murine Renca tumors, Setd2 knockdown and ATR inhibitor VE822 synergistically promoted cytosolic DNA sensing pathway, immune cell infiltration, and immune checkpoint protein expression. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or in combination with VE822 than Setd2 proficient tumors. SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients, but not in non-ICB-treated RCC patients. This study provides a mechanism-based guidance to develop more personalized combination therapy regimens for RCC patients with SETD2 mutations.

2023-07-25 | GSE234732 | GEO

ALDOB represents a potential prognostic biomarker for patients with clear cell renal cell carcinoma.

Project description: Not available

| S-EPMC10170270 | biostudies-literature

SNRPD3 preserves balanced MYCN-driven alternate splicing and represents a therapeutic vulnerability in neuroblastoma

Project description:SNRPD3 preserves balanced MYCN-driven alternate splicing and represents a therapeutic vulnerability in neuroblastoma

| PRJNA882396 | ENA

Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma.

Project description: Not available

| S-EPMC8741905 | biostudies-literature

KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant NSCLC

Project description:KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant NSCLC

| PRJEB90458 | ENA

Transcription profiling of shoot apices from Arabidopsis wild type, teb, atr, and teb atr mutant plants

Project description:Global gene expression patterns were compared among wild-type Col-0, teb, atr, teb atr of A. thaliana using shoot apices.

2008-04-01 | E-MEXP-1329 | biostudies-arrayexpress

ATR licenses PINK1-mediated mitophagy

Project description:Mitochondria are the central metabolic hub of the cell and their function is vital for cellular activities. Mitochondrial autophagy, or mitophagy, is a quality control mechanism to surveille the fitness and functionality of mitochondria and is therefore essential for life. Both mitochondrial dysfunction and malfunctional DNA damage response (DDR) are a major etiology for tissue impairment and aging. ATR has been shown mainly as a nuclear factor to conduct DNA damage response under DNA replication stress. Paradoxically, the human Seckel syndrome caused by ATR mutations is characterized by premature aging and neuropathies, suggesting a role of ATR in non-replicating tissues. Here we report a previously unknown yet direct role of ATR at mitochondria. We find that HSP90 chaperones ATR and PINK1 to mitochondria, where ATR interacts with and thereby stabilizes PINK1 docking at the mitochondrial translocase TOM/TIM complex as well as with the electron transport chain (ETC). ATR mutant cells are refractory to mitophagy initiation, which can be reverted by an ectopic expression of full length, but not ATR-interaction mutant, PINK1. ATR deletion alters mitochondrial dynamics and OXPHOS functions producing aberrantly high reactive oxygen species (ROS) that attack cytosolic macromolecules prior to damaging nuclear DNA. Intriguingly, pharmacological intervention of mitochondrial metabolism to prevent ROS overproduction can mute ATR-mediated nuclear DDR. This study demonstrates that ATR is an integrated component of the mitochondrial membrane to ensure mitochondrial fitness as a primary physiological function, which, together with its essential DDR function, safeguards the cell fate under physiological and genotoxic conditions.

2025-02-26 | GSE244464 | GEO

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