Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers
| Autor: | Elizabeth E. Hoskins, Kathryn A. Wikenheiser-Brokamp, Laura E. Hays, Lisa Wiesmüller, Grant D. Foglesong, Susan B. Olson, Winifred Keeble, Paul R. Andreassen, Susanne I. Wells, Helmut Hanenberg, Anne J. Lombardi, Allison J. Jacobs |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Cancer Research DNA End-Joining Repair DNA repair DNA damage medicine.medical_treatment Antineoplastic Agents Biology Poly(ADP-ribose) Polymerase Inhibitors Poly (ADP-Ribose) Polymerase Inhibitor Article Gene Knockout Techniques Mice Fanconi anemia hemic and lymphatic diseases Cell Line Tumor Spheroids Cellular medicine Tumor Cells Cultured Animals Humans Ku Autoantigen Cell Proliferation Cisplatin Mice Knockout Chemotherapy Fanconi Anemia Complementation Group D2 Protein Fanconi Anemia Complementation Group C Protein DNA Helicases nutritional and metabolic diseases Cancer medicine.disease Enzyme Activation Disease Models Animal Fanconi Anemia Phenotype Oncology Drug Resistance Neoplasm Head and Neck Neoplasms PARP inhibitor Immunology Cancer research Heterografts Poly(ADP-ribose) Polymerases medicine.drug DNA Damage |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 21(8) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design: Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc−/− mice, we sought to define Fanconi anemia–dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Results: Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi anemia–dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia–deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. Conclusions: The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual. Clin Cancer Res; 21(8); 1962–72. ©2015 AACR. |
| Databáze: | OpenAIRE |
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