Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response

Significance l -asparaginase (ASNase) is a critical component of treatment protocols for acute lymphoblastic leukemia (ALL). Although the cure rates have dramatically improved, the prognosis for patients with recurrent ALL remains poor. General control nonderepressible 2 (GCN2) plays a major role in cellular response to amino acid limitation. As inhibitors targeting GCN2 have been lacking, the potential of GCN2 inhibitors as cancer therapeutic agents remains unclear. Here we report potent GCN2 inhibitors that exhibit synergistic antiproliferative effects with ASNase in asparagine synthetase-low cancer. Our findings enhance the molecular understanding of the disrupted amino acid response caused by GCN2 inhibition under limited asparagine availability. Combined treatment with GCN2 inhibitors and ASNase shows promise for achieving improved outcomes in ALL and other types of cancer.