Citations 2
Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy
Claude, Rodney, Srivastava, Sankalp , Staschke, Kirk A., Fritz, Carlos A. Mellado, Chen, Shaoxiong, Liu, Lei, Zhong, Minghua, Lanman, Nadia A, Davé, Utpal P. , Batra, Sandeep , Zhou, Jiehao , Fang, Yue, Zhang, C , Kapur, Reuben , Wek, Ronald C., Zhang, Ji , Staschke, Kirk A. , Fritz, Carlos Mellado , Zhong, Minghua, Kothandaraman, Harish , Lanman, Nadia A. , Fan, Jing , Wek, Ronald C. , Zhang, Ji
JCI Insight | June 4, 2026 | Volume: 11 | Issue: 14 | Pages: No page available
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B and T cell lineages (B-ALL and T-ALL). Current therapy exploits ALL cells’ low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and the ASNS inhibitor ASX-173. Using a Kras G12D -driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2 –/– T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS hi leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high levels of ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.
Pediatric Acute Lymphoblastic Leukemia, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology
Inaba, Hiroto , Teachey, David T. , Annesley, Colleen , Batra, Sandeep , Beck, Jill C., Cooper, Stacy , Dallas, Mari , Oliveira, Satiro De , Kelly, Kara M. , Kohorst, Mira A. , Kutny, Matthew A. , Lee‐Miller, Cathy , Ludwig, Kathleen , Madden, Lisa, Maloney, Kelly W. , Massaro, Stephanie, Morocco, Perry , Muller, Brad, Murphy, Lindsey , Nardi, Valentina , Rossoff, Jenna , Schuettpelz, Laura G. , Sun, Jessica , Wong, Victor , Yanik, Gregory A. , Stehman, Katie, Inaba, Hiroto , Colace, Susan I. , Kitko, Carrie L. , Lacayo, Norman James , Mangum, David Spencer , McCall, David C. , Shah, Bijal , Awotiwon, Ajibola
Journal of the National Comprehensive Cancer Network | February 12, 2025 | Volume: 23 | Issue: 2 | Pages: 41-62
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.