ArticleThe Journal of clinical investigation2023
POLQ inhibition elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma via cGAS/STING signaling.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 53 citations in OpenAlex.
- A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: the phase 2 POLAR trial.Nature medicine · 2026Trial
- DNA polymerase theta (Polθ): a novel candidate for targeted cancer therapy.Cancer biology & therapy · 2026Review
- A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.Annals of medicine · 2026Review
- Targeting the DNA Damage Response in Cancer.MedComm · 2026Review
- The dual immune landscape of homologous recombination-deficient tumors: mechanisms and therapeutic implications.Cancer metastasis reviews · 2026Review
- EEPD1 Inhibition Unleashes Antitumor Immunity in Colorectal Cancer by Activating the cGAS-STING Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- POLQ promotes tumor progression and immunosuppression via ATM‑P53 signaling in endometrial cancer.Oncology reports · 2026Article
- Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas.Journal of advanced research · 2026Article
- Implications of DNA damage response and immunotherapy in tumor therapy.Cell communication and signaling : CCS · 2025Review
- RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors.Journal of medicinal chemistry · 2025Article
- Genome instability and crosstalk with the immune response.Genome medicine · 2025Review
- Epigenetic synthetic lethality as a cancer therapeutic strategy: synergy of experimental and computational approaches.Epigenomics · 2025Review
- Targeting RAD52 overcomes PARP inhibitor resistance in preclinicalbioRxiv : the preprint server for biology · 2025Article
- DNA-repair-driven cell death compels us to rethink cancer therapies.Nature reviews. Molecular cell biology · 2025Article
- Pembrolizumab and Olaparib (POLAR) Maintenance Therapy in Metastatic Pancreatic Cancer With or Without Homologous Repair Deficiency: A Biomarker Selected Phase II Trial.Research square · 2025Article
- Tumor irradiation induced immunogenic response: the impact of DNA damage induction and misrepair.Radiation oncology (London, England) · 2025Review
- The RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling.Nature communications · 2025Article
- The prognostic and predictive value of homologous recombination deficiency in gastrointestinal cancer.The oncologist · 2025Review
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that harbors mutations in homologous recombination-repair (HR-repair) proteins in 20%-25% of cases. Defects in HR impart a specific vulnerability to poly ADP ribose polymerase inhibitors and platinum-containing chemotherapy in tumor cells. However, not all patients who receive these therapies respond, and many who initially respond ultimately develop resistance. Inactivation of the HR pathway is associated with the overexpression of polymerase theta (Polθ, or POLQ). This key enzyme regulates the microhomology-mediated end-joining (MMEJ) pathway of double-strand break (DSB) repair. Using human and murine HR-deficient PDAC models, we found that POLQ knockdown is synthetically lethal in combination with mutations in HR genes such as BRCA1 and BRCA2 and the DNA damage repair gene ATM. Further, POLQ knockdown enhances cytosolic micronuclei formation and activates signaling of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), leading to enhanced infiltration of activated CD8+ T cells in BRCA2-deficient PDAC tumors in vivo. Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to blocking tumor growth while concurrently activating the cGAS-STING signaling pathway to enhance tumor immune infiltration, highlighting what we believe to be a new role for POLQ in the tumor immune environment.
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