ArticleThe Journal of clinical investigation2021
Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models.
Article in The Journal of clinical investigation, 2021. 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, 37 citations in OpenAlex.
- Tirapazamine sensitises hypoxic homologous recombination-proficient NSCLC to PARP inhibition.Cell death discovery · 2026Article
- Translational prioritization of strategies to overcome poly ADP-ribose polymerase inhibitor resistance in breast cancer based on systematic review of preclinical evidence.Discover oncology · 2026Review
- Review
- Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective.Biomarker research · 2026Review
- Model for Predicting Serious Hematological Adverse Events in Individuals With Ovarian Cancer Receiving Poly (Adenosine Diphosphate Ribose) Polymerase Inhibitor Treatment: Prospective Cohort Study.JMIR medical informatics · 2025Article
- Hypoxia Imaging as a Radiomics Signature in Tumors Using NovelbioRxiv : the preprint server for biology · 2025Article
- Navigating PARP Inhibitor Resistance in Ovarian Cancer: Bridging Mechanistic Insights To Clinical Translation.Current treatment options in oncology · 2025Review
- The distinct landscape of tumor immune microenvironment in homologous recombination deficient cancers.Biomarker research · 2025Review
- Reversing regulatory safeguards: Targeting the ATR pathway to overcome PARP inhibitor resistance.Molecular therapy. Oncology · 2025Review
- Tumour hypoxia in driving genomic instability and tumour evolution.Nature reviews. Cancer · 2025Review
- Hypoxia-Responsive Prodrug of ATR Inhibitor, AZD6738, Selectively Eradicates Treatment-Resistant Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours.Frontiers in oncology · 2024Review
- Mechanism of PARP inhibitor resistance and potential overcoming strategies.Genes & diseases · 2024Review
- Review
- Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer.Nature communications · 2023Article
- Multi-scale characterisation of homologous recombination deficiency in breast cancer.Genome medicine · 2023Article
- Overcoming the Impact of Hypoxia in Driving Radiotherapy Resistance in Head and Neck Squamous Cell Carcinoma.Cancers · 2022Review
- Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers.NPJ breast cancer · 2022Article
- The importance of hypoxia in radiotherapy for the immune response, metastatic potential and FLASH-RT.International journal of radiation biology · 2022Review
- Therapeutic targeting of the hypoxic tumour microenvironment.Nature reviews. Clinical oncology · 2021Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells. Mechanistically, we identify reduced ROS-induced DNA damage as the cause for the observed resistance. To determine the contribution of hypoxia to PARPi resistance in tumors, we used the hypoxic cytotoxin tirapazamine to selectively kill hypoxic tumor cells. We found that the selective elimination of hypoxic tumor cells led to a substantial antitumor response when used with PARPi compared with that in tumors treated with PARPi alone, without enhancing normal tissue toxicity. Since human breast cancers with BRAC1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARPi, then eliminating hypoxic tumor cells should enhance the efficacy of PARPi therapy.
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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.