DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced marked resistance to Ara-C, but not to vincristine and daunorubicin, indicating the involvement of DCK expression in the Ara-C sensitivity of BCP-ALL.
However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity.
Reexpression of dCk could increase the cellular ara-CTP concentrations and the sensitivity to ara-C. A total of 17 pediatric patients with refractory acute lymphocytic leukemia (ALL) received a continuous infusion of 5-Aza-C at 150 mg/m2 daily for 5 days after not responding to (13/17) or relapsing from (4/17) an HDara-C regimen (3 g/m2 over 3 h, every 12 h, x 8 doses).