ArticleCancer research2023
SETD2 Deficiency Confers Sensitivity to Dual Inhibition of DNA Methylation and PARP in Kidney Cancer.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 17 citations in OpenAlex.
- The dual immune landscape of homologous recombination-deficient tumors: mechanisms and therapeutic implications.Cancer metastasis reviews · 2026Review
- Histone Methylation and Chromatin Remodeling in Non-Small Cell Lung Cancer: Mechanisms of Oncogenesis and Emerging Therapeutic Strategies.Biomedicines · 2026Review
- Alkylating agents activate an SLFN11-dependent vulnerability that confers PARP-1 inhibitor sensitivity in kidney cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Unveiling the epigenetic landscape: transforming renal cell carcinoma treatment.Clinical epigenetics · 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
- ULK1-driven autophagy modulation alters tumor-promoting pathways in triple-negative breast cancer.Medical oncology (Northwood, London, England) · 2026Article
- Lessons learned in linking PROTACs from discovery to the clinic.Nature reviews. Chemistry · 2026Review
- PARP inhibitors across different malignancies: clinical applications, resistance mechanisms, and strategies to enhance efficacy through combination therapies.Frontiers in cell and developmental biology · 2026Review
- Histone methyltransferase SETD2 regulates TKT expression and mediates glycolysis to suppress lung adenocarcinoma progression and improve chemosensitivity.American journal of cancer research · 2026Article
- The Role of Homologous Recombination Deficiency (HRD) in Renal Cell Carcinoma (RCC): Biology, Biomarkers, and Therapeutic Opportunities.Current oncology (Toronto, Ont.) · 2025Review
- Beyond tumour suppression: cGAS-STING pathway in urologic malignancies: Context-dependent duality and therapeutic implications.Clinical and translational medicine · 2025Review
- Phospho-TRIM21 orchestrates RPA2 ubiquitination switch to promote homologous recombination and tumor radio/chemo-resistance.Oncogene · 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
- SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.Genome biology · 2025Article
- The activation of cGAS-STING pathway offers novel therapeutic opportunities in cancers.Frontiers in immunology · 2025Review
- Article
- SETD2 and EZH2: Two epigenetic drivers of prostate cancer.Journal of Cancer · 2025Review
- Metabolism and epigenetics in cancer: toward personalized treatment.Frontiers in endocrinology · 2025Review
- Systematic multiomics analysis and in vitro experiments suggest that ITGA5 could serve as a promising therapeutic target for ccRCC.Cancer cell international · 2024Article
- A Multi-Omics Prognostic Model Capturing Tumor Stemness and the Immune Microenvironment in Clear Cell Renal Cell Carcinoma.Biomedicines · 2024Article
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
SETD2 deficiency alters the epigenetic landscape by causing depletion of H3K36me3 and plays an important role in diverse forms of cancer, most notably in aggressive and metastatic clear-cell renal cell carcinomas (ccRCC). Development of an effective treatment scheme targeting SETD2-compromised cancer is urgently needed. Considering that SETD2 is involved in DNA methylation and DNA repair, a combination treatment approach using DNA hypomethylating agents (HMA) and PARP inhibitors (PARPi) could have strong antitumor activity in SETD2-deficient kidney cancer. We tested the effects of the DNA HMA 5-aza-2'-dexoxydytidine (DAC), the PARPi talazoparib (BMN-673), and both in combination in human ccRCC models with or without SETD2 deficiency. The combination treatment of DAC and BMN-673 synergistically increased cytotoxicity in vitro in SETD2-deficient ccRCC cell lines but not in SETD2-proficient cell lines. DAC and BMN-673 led to apoptotic induction, increased DNA damage, insufficient DNA damage repair, and increased genomic instability. Furthermore, the combination treatment elevated immune responses, upregulated STING, and enhanced viral mimicry by activating transposable elements. Finally, the combination effectively suppressed the growth of SETD2-deficient ccRCC in in vivo mouse models. Together, these findings indicate that combining HMA and PARPi is a promising potential therapeutic strategy for treating SETD2-compromised ccRCC. SIGNIFICANCE: SETD2 deficiency creates a vulnerable epigenetic status that is targetable using a DNA hypomethylating agent and PARP inhibitor combination to suppress renal cell carcinoma, identifying a precision medicine-based approach for SETD2-compromised cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.