范可尼贫血 (FA) 是一种罕见的遗传性疾病，由 FA/BRCA 通路失活突变引起，该通路对于 DNA 链间交联 (ICL) 的有效修复至关重要。该疾病的特点是先天性异常、进行性骨髓衰竭以及生命早期患恶性肿瘤的风险增加，特别是头颈鳞状细胞癌 (HNSCC)。虽然 ICL 诱导顺铂联合放疗是 HNSCC 治疗的主要手段，但顺铂对于 FA-HNSCC 患者是禁忌的。这种困境需要确定 FA-HNSCC 患者能够耐受的新治疗方式。为了确定可药物靶标，之前在 FA 和非 FA 肿瘤来源的 HNSCC 衍生细胞系中进行了基于 siRNA 的遗传筛选。在此，我们报告由 RRM1 和 RRM2 亚基组成的核糖核苷酸还原酶 (RNR) 复合物被确定为 FA 和非 FA HNSCC 的治疗靶点。虽然非 FA HNSCC 细胞对 RNR 耗竭的反应不同，但 FA-HNSCC 细胞始终被发现过敏。使用 2', 2'-二氟 2' 脱氧胞苷 (dFdC)（也称为吉西他滨）在药理学上证实了这一见解，吉西他滨是一种临床使用的核苷酸类似物，是 RNR 复合物的有效抑制剂。重要的是，虽然顺铂暴露对 Fancg-/- 小鼠的造血干和祖细胞室显示出严重、持久的毒性，但吉西他滨的耐受性良好，并且仅产生轻微、短暂的影响。综上所述，我们的数据表明基于吉西他滨的放化疗可以作为 Fanconi 患者 HNSCC 的替代治疗方法，值得临床测试。© 2024。作者。

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.© 2024. The Author(s).