Inhibiting PI3K/mTOR, SIRT2 Pathways May Be Effective in Treating Aggressive AML

Acute myeloid leukemia (AML) is an aggressive hematological cancer with a low 5-year survival rate (24%) and few therapeutic options. However, a new study suggests thatcombination treatment using a PI3K/mTOR inhibitor and sirtuin 2 (SIRT2) inhibitor could make for a successful drug target for AML, according to the results of a study published in Cancer Medicine. The study results showed that the combination treatment effectively stopped the proliferation of AML cells.

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“The treatment of leukemia can be significantly improved through the scientific and rational combination of drugs,” write study authors in the publication. “This approach has been shown to offer high efficacy while also minimizing tolerance issues during the treatment process.”

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR) signaling pathway is activated in many cancer types. mTOR is a protein kinase that phosphorylates other proteins that promote tumor cell growth; targeting—or rather inhibiting—the PI3K/mTOR signaling pathway could prove beneficial to reducing AML cell development; however, these inhibitors are not commonly used for hematologic cancers.

Investigators used a bioinformatics analysis to screen for changes in AML gene expression to understand how a PI3K/mTOR inhibitor (VS-5584) works with SirReal2, a SIRT2 inhibitor, to reduce cancer growth, confirming that a PI3K/AKT inhibitor effectively suppresses thePI3K/AKT pathway in AML cells and “results in alterations in the expression of downstream signaling molecules,” study authors wrote.

Using proteomics analysis, investigators observed that modulating the gene expression in these proteins reduced AML cell proliferation by repressing the PI3K/mTOR pathway and stimulating the P53 signaling pathway. The P53 signaling pathway regulates the cell cycle, apoptosis, and cell development, and stimulating this pathway induced apoptosis in the leukemia cells.

More specifically, the analysis highlighted that VS-5584 down-regulated 287 proteins and up-regulated 71 proteins. Down-regulated proteins were largely related to tumor cell cycle regulation and apoptosis, while up-regulated proteins were mainly associated with cell cycle, glycan degradation, and RNA degradation.

Like PI3K/mTOR, SIRT2 is also implicated in various cancers; it is suggested to promote AML leukemic cell proliferation via metabolic reprogramming. Moreover, SIRT2 may improve tumor cell sensitivity to VS-5584, leading to more effective suppression of AML cell proliferation than VS-5584 alone.

The duo could be a feasible treatment option because it has not been shown to increase body weight in mouse models, despite small molecule inhibitors being associated with toxicity and adverse events (AEs). Further, dose and timing matter. In this study, a low concentration of VS-5584 proved effective at suppressing tumor growth, so the treatment should be administered in a dose-dependent manner.

“VS-5584 may induce AML cell cycle arrest and apoptosis by modulating signaling pathways involved,” study authors wrote. “It is crucial to prioritize fundamental research endeavors aimed at developing novel therapeutic approaches.”

Reference

Luo Y, Zhao H, Zhu J, et al. SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells. Cancer Med. 2023;00:1-17. doi:10.1002/cam4.6480