ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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Who cites it
107 citing papers in PubMed, 152 citations in OpenAlex.
- Systematic analyses to explore kinase gene set-based signature in glioma, in which WEE1 contributes to tumor progression.Discover oncology · 2026Article
- Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective.Biomarker research · 2026Review
- Comparing and combining xevinapant with ATR and PARP inhibition for the radiosensitization of HPV-negative HNSCC cells.Scientific reports · 2026Article
- Targeting Undruggable Proteins: The siRNA Revolution Beyond Small Molecules - Advances, Challenges, and Future Prospects in Therapeutic Innovation.Current gene therapy · 2026Review
- PARPs and PARP inhibitors: molecular mechanisms and clinical applications.Molecular biomedicine · 2025Review
- Radiosensitization Effect of PARP Inhibitor Talazoparib Involves Decreasing Mitochondrial Membrane Potential and Induction of Cellular Senescence.Current issues in molecular biology · 2025Article
- Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer.Molecular cancer therapeutics · 2025Article
- Recent Advancement in Drug Targeting Therapies in the Treatment of Pancreatic Cancer.Current pharmaceutical design · 2025Review
- Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review.Cancer biology & therapy · 2024Review
- Article
- Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma.Nature communications · 2024Article
- DDB2 expression lights the way for precision radiotherapy response in PDAC cells, with or without olaparib.Cell death discovery · 2024Article
- The Potential for Targeting GCancers · 2024Review
- BRCAness, DNA gaps, and gain and loss of PARP inhibitor-induced synthetic lethality.The Journal of clinical investigation · 2024Review
- The preclinical gap in pancreatic cancer and radiotherapy.Disease models & mechanisms · 2024Article
- Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer.BJC reports · 2024Article
- Mechanisms of PARP-Inhibitor-Resistance in BRCA-Mutated Breast Cancer and New Therapeutic Approaches.Cancers · 2023Review
- Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1.Clinical and translational radiation oncology · 2023Article
- G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells.Radiation oncology (London, England) · 2023Article
- Targeting replication stress in cancer therapy.Nature reviews. Drug discovery · 2023Review
47 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
purposeWhile the addition of radiation to chemotherapy improves survival in patients with locally advanced pancreatic cancer, more effective therapies are urgently needed. Thus, we investigated the radiosensitizing efficacy of the novel drug combination of Wee1 and PARP1/2 inhibitors (AZD1775 and olaparib, respectively) in pancreatic cancer. EXPERIMENTAL
designRadiosensitization of AsPC-1 or MiaPaCa-2 human pancreatic cancer cells was assessed by clonogenic survival and tumor growth assays. Mechanistically, the effects of AZD1775, olaparib, and radiation on cell cycle, DNA damage (γH2AX), and homologous recombination repair (HRR) were determined.
resultsTreatment of AsPC-1 and MiaPaCa-2 cells with either AZD1775 or olaparib caused modest radiosensitization, whereas treatment with the combination significantly increased radiosensitization. Radiosensitization by the combination of AZD1775 and olaparib was associated with G2 checkpoint abrogation and persistent DNA damage. In addition, AZD1775 inhibited HRR activity and prevented radiation-induced Rad51 focus formation. Finally, in vivo, in MiaPaCa-2-derived xenografts, olaparib did not radiosensitize, whereas AZD1775 produced moderate, yet significant, radiosensitization (P < 0.05). Importantly, the combination of AZD1775 and olaparib produced highly significant radiosensitization (P < 0.0001) evidenced by a 13-day delay in tumor volume doubling (vs. radiation alone) and complete eradication of 20% of tumors.
conclusionsTaken together, these results demonstrate the efficacy of combined inhibition of Wee1 and PARP inhibitors for radiosensitizing pancreatic cancers and support the model that Wee1 inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization through inhibition of HRR and abrogation of the G2 checkpoint, ultimately resulting in unrepaired, lethal DNA damage and radiosensitization. Clin Cancer Res; 20(19); 5085-96. ©2014 AACR.
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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.