Gemcitabine as chemotherapy of head and neck cancer in Fanconi anemia patients

Fanconi anemia (FA) is a rare hereditary disease resulting from an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by congenital abnormalities, progressing bone marrow failure, and an increased risk of...

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Veröffentlicht in:Oncogenesis (New York, NY) Jg. 13; H. 1; S. 26 - 10
Hauptverfasser: van Harten, Anne M., Shah, Ronak, de Boer, D. Vicky, Buijze, Marijke, Kreft, Maaike, Song, Ji-Ying, Zürcher, Lisa M., Jacobs, Heinz, Brakenhoff, Ruud H.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 11.07.2024
Nature Publishing Group
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Anemia
Apoptosis
Breast cancer
Cell Biology
Chemoradiotherapy
Chemotherapy
Cisplatin
DNA repair
Fanconi syndrome
Gemcitabine
Genetic screening
Head & neck cancer
Head and neck carcinoma
Hemopoiesis
Hereditary diseases
Human Genetics
Internal Medicine
Malignancy
Medicine
Medicine & Public Health
Nucleotide analogs
Oncology
Patients
Radiation therapy
Ribonucleotide reductase
siRNA
Squamous cell carcinoma
Therapeutic targets
Toxicity
Tumor cell lines
ISSN:2157-9024, 2157-9024
Online-Zugang:Volltext
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Zusammenfassung:Fanconi anemia (FA) is a rare hereditary disease resulting from an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by congenital abnormalities, progressing bone marrow failure, and an increased risk of developing malignancies early in life, in particular head and neck squamous cell carcinoma (HNSCC). While ICL-inducing cisplatin combined with radiotherapy is a mainstay of HNSCC treatment, cisplatin is contra-indicated for FA-HNSCC patients. This dilemma necessitates the identification of novel treatment modalities tolerated by FA-HNSCC patients. To identify druggable targets, an siRNA-based genetic screen was previously performed in HNSCC-derived cell lines from FA and non-FA tumor origin. Here, we report that the Ribonucleotide Reductase (RNR) complex, consisting of the RRM1 and RRM2 subunits, was identified as a therapeutic target for both, FA and non-FA HNSCC. While non-FA HNSCC cells responded differentially to RNR depletion, FA-HNSCC cells were consistently found hypersensitive. This insight was confirmed pharmacologically using 2′, 2′-difluoro 2′deoxycytidine (dFdC), also known as gemcitabine, a clinically used nucleotide analog that is a potent inhibitor of the RNR complex. Importantly, while cisplatin exposure displayed severe, long-lasting toxicity on the hematopoietic stem and progenitor compartments in Fancg−/− mice, gemcitabine was well tolerated and had only a mild, transient impact. Taken together, our data implicate that gemcitabine-based chemoradiotherapy could serve as an alternative HNSCC treatment in Fanconi patients, and deserves clinical testing.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2157-9024
2157-9024
DOI:10.1038/s41389-024-00525-2