ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 102 citations in OpenAlex.
- Phase 2 Trial of Neoadjuvant FOLFIRINOX and Intensity Modulated Radiation Therapy Concurrent With Fixed-Dose Rate-Gemcitabine in Patients With Borderline Resectable Pancreatic Cancer.International journal of radiation oncology, biology, physics · 2020Trial
- Genome-wide CRISPR screen identifies PKMYT1 inhibition as a synthetic lethal vulnerability in IDH1-mutant glioma.Cancer letters · 2026Article
- Dual CHK1 and WNT Inhibition as a Synergistic Therapy for Gastrointestinal Neuroendocrine Carcinoma.Cancer research communications · 2026Article
- Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons.Cell death & disease · 2025Article
- MK-8776 and Olaparib Combination Acts Synergistically in Hepatocellular Carcinoma Cells, Demonstrating Lack of Adverse Effects on Liver Tissues in Ovarian Cancer PDX Model.International journal of molecular sciences · 2025Article
- Olaparib Combined with DDR Inhibitors Effectively Prevents EMT and Affects miRNA Regulation inInternational journal of molecular sciences · 2025Article
- Recent Advancement in Drug Targeting Therapies in the Treatment of Pancreatic Cancer.Current pharmaceutical design · 2025Review
- The Potential for Targeting GCancers · 2024Review
- Review
- Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives.Clinical and translational radiation oncology · 2023Review
- Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment.World journal of gastroenterology · 2022Review
- Article
- Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients.International journal of molecular sciences · 2022Review
- ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.Oncogene · 2022Article
- Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer.Neoplasia (New York, N.Y.) · 2022Article
- The BET Inhibitor JQ1 Potentiates the Anticlonogenic Effect of Radiation in Pancreatic Cancer Cells.Frontiers in oncology · 2022Article
- Translation of DNA Damage Response Inhibitors as Chemoradiation Sensitizers From the Laboratory to the Clinic.International journal of radiation oncology, biology, physics · 2021Article
- CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.Cell reports · 2021Article
- Review
- Tailor-Made Nanomaterials for Diagnosis and Therapy of Pancreatic Ductal Adenocarcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Review
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
Abstract
purposeThe combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Checkpoint kinase 1 (Chk1) inhibitor MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models. EXPERIMENTAL
designWe tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)-proficient and -deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776.
resultsWe found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not -deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose-limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer.
conclusionsTogether, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer.
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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.