Exploiting CDA-Mediated metabolism of 5fdC to overcome cytarabine resistance in Malignant myeloid cells leukemia

Myeloid leukemia (ML) remains a therapeutic challenge due to the frequent development of resistance to frontline cytosine arabinoside (AraC). One of a key driver of this resistance is the overexpression of cytidine deaminase (CDA), which inactivates AraC. Here, we present a counterintuitive therapeutic strategy that exploits this very resistance pathway to overcome chemoresistance. We demonstrate that the 5-formyl-2'-deoxycytidine (5fdC) is activated by CDA into the cytotoxic metabolite 5-formyl-2'-deoxyuridine (5fdU) in AraC resistant leukemia cells. This CDA mediated metabolism, which undermines AraC therapy, becomes a critical vulnerability for resistant cells. In both in vitro AraC resistant cell lines and CDA overexpressing animal models, the conversion of 5fdC to 5fdU potently induces DNA damage and triggers Apoptosis. Consequently, 5fdC exhibits enhanced and selective cytotoxicity specifically against AraC resistant leukemia cells, while showing comparatively less effect on sensitive cells. Our work unveils a novel metabolic targeting approach, turning a key resistance mechanism into a therapeutic Achilles' heel for treating refractory myeloid leukemia.