Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy

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Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B- and T-cell lineages. 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 a novel ASNS inhibitor designated ASX-173. Using a KrasG12D-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-high leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.

Authors

Rodney Claude, Sankalp Srivastava, Kirk A. Staschke, Carlos A. Mellado Fritz, Shaoxiong Chen, Lei Liu, Minghua Zhong, Harish Kothandaraman, Nadia A. Lanman, Utpal P. Davé, Sandeep Batra, Jiehao Zhou, Yue Fang, Chi Zhang, Reuben Kapur, Jing Fan, Ronald C. Wek, Ji Zhang