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

Abstract

Abstract Fanconi anemia (FA) is a rare hereditary disease characterized by an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by progressing bone marrow failure, congenital abnormalities and an increased risk to develop malignancies early in life, in particular head and neck squamous cell carcinoma (HNSCC). While ICL-inducing cisplatin combined with radiotherapy are a mainstay of HNSCC treatment, cisplatin is contraindicated 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 performed previously 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 analogue that is a potent inhibitor of the RNR complex. Importantly, while cisplatin exposure displayed a 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.