2. Academic Validation
  3. Connectivity-map unveils Gemcitabine's efficacy in overcoming nelarabine resistance in T-cell acute lymphoblastic leukemia

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

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: liubing520@gdpu.edu.cn.
  • 6 Center for Drug Research and Development, Guangdong Pharmaceutical University, China. Electronic address: min.wei@gdpu.edu.cn.
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.

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