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

  • Biochem Biophys Res Commun. 2025 Jul 8:769:151971. doi: 10.1016/j.bbrc.2025.151971.
Ximei Wu  1 ,  Chunxu Lin  2 ,  Hui Wang  1 ,  Jingjing Gao  1 ,  Suchang Chen  1 ,  Zitao Zhou  3 ,  Luyong Zhang  4 ,  Bing Liu  5 ,  Min Wei  6
Affiliations
  • 1. Center for Drug Research and Development, Guangdong Pharmaceutical University, China; School of Pharmacy, Guangdong Pharmaceutical University, China.
  • 2. The Eighth People's Hospital of Longgang District, Shenzhen, China.
  • 3. School of Pharmacy, Guangdong Pharmaceutical University, China.
  • 4. Center for Drug Research and Development, Guangdong Pharmaceutical University, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, China.
  • 5. School of Pharmacy, Guangdong Pharmaceutical University, China. Electronic address: [email protected].
  • 6. Center for Drug Research and Development, Guangdong Pharmaceutical University, China. Electronic address: [email protected].
PMID: 40354678 DOI: 10.1016/j.bbrc.2025.151971
Abstract

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.

Keywords
Chemoresistance; Gemcitabine; Nelarabine; T-ALL; T-cell acute lymphoblastic leukemia.
Products