Connectivity-map unveils Gemcitabine's efficacy in overcoming nelarabine resistance in T-cell acute lymphoblastic...

Resistance to Nelarabine, the primary FDA-approved therapy for relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL), is a major obstacle in this high-risk pediatric malignancy. To identify alternative therapies, we have developed two nelarabine-resistant T-ALL cell models and utilized the Connectivity Map (CMap) database to screen for compounds reversing resistance-associated expression profiles., Among the inhibitors screened, gemcitabine emerged as a lead candidate by inhibiting cell proliferation, inducing apoptosis, and suppressing DNA replication in resistant T-ALL cells. RNA sequencing revealed global transcriptomic changes in cells treated with gemcitabine, which were further validated by qRT-PCR. Critically, gemcitabine effectively controlled bone marrow tumor growth in an NSG mouse model with good tolerability. These findings highlight the potential of gemcitabine as a promising therapeutic strategy to overcome nelarabine-resistance in T-ALL.