Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response
Menée à l'aide de cellules de leucémie lymphoblastique aiguë et à l'aide d'un modèle murin, cette étude montre que l'inhibition de la kinase GCN2 sensibilise à la L-asparaginase (un antileucémique) les cellules cancéreuses exprimant faiblement l'asparagine synthétase et réduit ainsi la synthèse de nouvelles protéines
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.General control nonderepressible 2 (GCN2) plays a major role in the cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, the contribution of GCN2 to cancer cell survival and proliferation is poorly understood. In this study, we generated GCN2 inhibitors and demonstrated that inhibition of GCN2 sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the antileukemic agent l-asparaginase (ASNase) in vitro and in vivo. We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of ASNS, resulting in reduced levels of de novo protein synthesis. Comprehensive gene-expression profiling revealed that combined treatment with ASNase and GCN2 inhibitors induced the stress-activated MAPK pathway, thereby triggering apoptosis. By using cell-panel analyses, we also showed that acute myelogenous leukemia and pancreatic cancer cells were highly sensitive to the combined treatment. Notably, basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer.