ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
SETD2 Loss and ATR Inhibition Synergize to Promote cGAS Signaling and Immunotherapy Response in Renal Cell Carcinoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 12 citations in OpenAlex.
- Targeting the DNA Damage Response in Cancer.MedComm · 2026Review
- SETD2 Deficiency Drives Mitochondrial DNA Leakage and Creates a Druggable Dependency on BCL-xL in Clear Cell Renal Cell Carcinoma.Cancer research · 2026Article
- Transient ATR inhibition following ionizing radiation enhances immune-mediated antitumor response and survival.bioRxiv : the preprint server for biology · 2026Article
- Essential genetic mutations impair DNA damage repair and modulate tumor immune microenvironment in ccRCC.MedScience · 2026Review
- Emerging roles for the epigenetic modifiers PBRM1 SETD2 and BAP1 in clear cell renal cell carcinoma pathogenesis and prognosis beyond VHL.Discover oncology · 2026Review
- The cGAS-STING pathway in cancer immunotherapy: prognostic value and therapeutic potential.Frontiers in immunology · 2026Review
- The Role of Homologous Recombination Deficiency (HRD) in Renal Cell Carcinoma (RCC): Biology, Biomarkers, and Therapeutic Opportunities.Current oncology (Toronto, Ont.) · 2025Review
- Mechanisms of Ferroptosis-Related Genes in Gallbladder Cancer Based on Bioinformatics Analysis.Molecular biotechnology · 2025Article
- Loss of SETD2 in wild-type VHL clear cell renal cell carcinoma sensitizes cells to STF-62247 and leads to DNA damage, cell cycle arrest, and cell death characteristic of pyroptosis.Molecular oncology · 2025Article
- PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.Cell death discovery · 2025Article
- The fall of the genome protectors triad: PBRM1, SETD2, and BAP1's impact on metabolism and immunity in clear cell renal cell carcinoma.Frontiers in cell and developmental biology · 2025Review
- Mechanisms of ferroptosis and targeted therapeutic approaches in urological malignancies.Cell death discovery · 2024Review
- Catalytic activity of Setd2 is essential for embryonic development in mice: establishment of a mouse model harboring patient-derived Setd2 mutation.Frontiers of medicine · 2024Article
- SETD2 in cancer: functions, molecular mechanisms, and therapeutic regimens.Cancer biology & medicine · 2024Article
- Structural variants involving MLLT10 fusion are associated with adverse outcomes in pediatric acute myeloid leukemia.Blood advances · 2024Article
- Targeting ATR in patients with cancer.Nature reviews. Clinical oncology · 2024Review
- Mathematical and Machine Learning Models of Renal Cell Carcinoma: A Review.Bioengineering (Basel, Switzerland) · 2023Review
- Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential candidacy for adjuvant immune checkpoint inhibition.F1000Research · 2023Article
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
purposeImmune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it. EXPERIMENTAL
designWe investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC.
resultsATR inhibition activated the cyclic GMP-AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)-dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory cytokines and immune checkpoints. Among the common RCC genotypes, SETD2 loss is associated with preferential ATR activation and sensitizes cells to ATR inhibition. SETD2 knockdown promoted the cytosolic DNA-sensing pathway in response to ATR inhibition. Treatment with the ATR inhibitor VE822 concurrently upregulated immune cell infiltration and immune checkpoint expression in Setd2 knockdown Renca tumors, providing a rationale for ATR inhibition plus ICB combination therapy. Setd2-deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or combination therapy with VE822 than Setd2-proficient tumors. Moreover, SETD2 mutations were associated with a higher response rate and prolonged overall survival in patients with ICB-treated RCC but not in patients with non-ICB-treated RCC.
conclusionsSETD2 loss and ATR inhibition synergize to promote cGAS signaling and enhance immune cell infiltration, providing a mechanistic rationale for the combination of ATR and checkpoint inhibition in patients with RCC with SETD2 mutations.
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Registered trials
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