Arginine Depletion plus GCN2 Inhibition Sensitizes HCC Cells to Senolytic Therapies

Cancer cells exhibit distinct metabolic programs that support their enhanced need for energy production. One such program involves suppression of key urea cycle enzymes, which leads to dependence on exogenous arginine (Arg). Response to available exogenous amino acids like Arg during nutrient sufficiency activates multiple signaling pathways to support protein synthesis, while the integrated stress response is activated during times of nutrient deprivation. Missiaen, Anderson, and colleagues investigated the cellular responses of hepatocellular carcinoma (HCC), a disease with very few treatment options, to consistent urea cycle repression and subsequent Arg auxotrophy, revealing that severe HCC disease is associated with urea cycle suppression. Investigation into the dependence of cell proliferation and viability on Arg import showed impaired DNA synthesis upon Arg removal from culture media as well as upregulation of cationic amino acid solute carrier (SLC) transporters, especially SLC7A1. Depletion of SLC7A1 reduced intracellular Arg levels, cell proliferation, and in vivo HCC tumor growth, suggesting dependence of HCC on SLC7A1 for Arg uptake. In addition to impaired cell growth upon exogenous Arg deprivation, cell cycle arrest was observed with no noticeable changes to apoptosis, and further studies indicated this cell cycle arrest is, in part, mediated by the general control nonderepressible 2 (GCN2) kinase–dependent integrated stress response involving p21. Furthermore, GCN2 inhibition after prolonged Arg depletion induced senescence and sensitivity to senolytic inhibition, with preclinical models indicating combined use of Arg restriction, GCN2 inhibition, and senolytic therapy increased apoptosis and reduced tumor growth both in vitro and in vivo. In summary, this study shows that urea cycle suppression in HCC is correlated with an induction in exogenous Arg dependence that can sensitize HCC cells to senolytic treatments when GCN2 is also inhibited, suggesting use of combination therapy to target this axis to improve treatment strategies for HCC.

Missiaen R, Anderson NM, Kim LC, Nance B, Burrows M, Skuli N, et al. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment. Cell Metab 2022;34:1151–67.e7.

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