Investigators identify potential dual targets in prostate cancer

Recently published preclinical data suggests that the depletion of GCN2 and loss of p53 enhances cell death in prostate cancer, presenting a potential novel targeting mechanism that could be leveraged in the development of new therapeutic strategies.¹

The deficiency of GCN2 induced activation of p53 signaling.

The data were published in the journal Science Signaling.

Previous work from the team of investigators had uncovered that the eIF2 kinase GCN2 and the integrated stress response played a key role in supporting cell survival and tumor progression.² In this process, GCN2 signals cells to fuel tumor growth when the availability of intracellular amino acids is reduced, thus maintaining amino acid homeostasis. The authors posited that targeting GCN2 would result in reduced amino acid availability, and therefore subsequent tumor cell death.

"We were only partially correct," said Kirk A. Staschke, PhD, an assistant research professor of biochemistry and molecular biology and the Ronald C. Wek, PhD, Showalter Professor of Biochemistry at the Indiana University School of Medicine, in a news release on the findings.³ "Inhibiting GCN2 did slow the growth of the tumor cells, but it didn’t kill them. That's when we discovered the cancer has a backup plan."

This “backup plan” involves the protein p53.

The current study showed that although inhibition of GCN2 depleted amino acids used in purine nucleotide synthesis, the deficiency induced activation of p53 signaling.

According to the authors, “This p53 activation occurred through GCN2 inhibition–dependent reductions in purine nucleotides that impaired ribosome biogenesis and, consequently, induced the impaired ribosome biogenesis checkpoint.”

When p53 was activated, it induced cell cycle arrest and senescence that enabled the proliferation of prostate cancer cells that were depleted of GCN2.

In prostate cancer cell lines, organoids, and xenograft models, depletion of GCN2 and loss of p53 reduced proliferation of tumors and enhanced cell death. Additionally, data showed that in mice, the effect of GCN2 inhibition was more pronounced in tumors that were deficient in p53.

"The current study exploits metabolic vulnerabilities unique to prostate cancer to starve it for essential nutrients and kill these tumor cells," Staschke added in the news release.³

The authors suggest that dual targeting of these mechanisms may serve as a promising therapeutic strategy to inhibit prostate cancer growth.

Thus, they concluded, “Our findings highlight the coordinated interplay between GCN2 and p53 regulation during nutrient stress and provide insight into how they could be targeted in developing new therapeutic strategies for [prostate cancer].”

References

1. Cordova RA, Sommers NR, Law AS, et al. Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer. Sci Signal. 2024;17(864):eadp1375. doi:10.1126/scisignal.adp1375

2. Cordova RA, Misra J, Amin PH, et al. GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis. Elife. 2022:11:e81083. doi:10.7554/eLife.81083

3. Researchers find new way to 'starve' prostate cancer tumors at the cellular level. News release. Indiana University. December 18, 2024. Accessed December 20, 2024. https://www.newswise.com/articles/researchers-find-new-way-to-starve-prostate-cancer-tumors-at-the-cellular-level