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Preclinical Data Point to GCN2 Inhibition as a Potential Treatment Strategy in Hepatocellular Carcinoma

By: Celeste L. Dixon
Posted: Friday, September 30, 2022

Hepatocellular carcinomas could potentially be treated by one or some combination of four novel strategies: targeting SLC7A1, a cationic amino acid transporter; restricting arginine, an amino acid; inhibiting GCN2, a kinase; and using senolytic agents, drugs that eliminate senescent cells (ie, senotherapy). Preclinical models confirm that these strategies promote hepatocellular carcinoma cell apoptosis and tumor regression, said M. Celeste Simon, PhD, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues in Cell Metabolism.

“Essentially, we identified a metabolic property of most liver cancers that offers the possibility of treating these cancers effectively, using drugs that are already approved or in development,” commented Dr. Simon in a University of Pennsylvania press release.

According to the investigators, hepatocellular carcinomas are marked by the metabolic property of urea cycle loss, and these cancers “consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine.” In other words, the hepatocellular carcinoma cells are “arginine-starved” and depend on this amino acid to survive.

Supporting this dependence is SLC7A1, Dr. Simon and co-investigators were surprised to find. Targeting SLC7A1 could be an element of hepatocellular carcinoma treatment, because inhibiting it slows hepatocellular carcinoma cell growth both in vitro and in vivo, they noted.

Additionally, they discussed, depriving the cancer cells of arginine creates an “integrated stress response that promotes hepatocellular carcinoma cell-cycle arrest and quiescence, [which is] dependent on GCN2.” If those arginine-deprived cells are also deprived of GCN2, a senescent phenotype is promoted, one that makes the cells vulnerable to senolytic compounds,” the team wrote.

Currently, then, it appears that treatment with arginine restriction combined with GCN2iB, which inhibits GCN2, and ABT-263, which inhibits BCL2, may result in hepatocellular carcinoma cell death. “Future studies will design strategies to positively affect arginine availability for immune cells to augment antitumor activities,” concluded Dr. Simon and colleagues.

Disclosure: The study authors’ disclosure information can be found at cell.com.


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