Oncotarget: Akt Antagonist Drug and Th1 Cytokines Combat Breast Cancer
Channel: Oncotarget
Date: 2021-07-13

Oncotarget published this top-performing research paper on July 28, 2020, entitled, “Th1 cytokines in conjunction with pharmacological Akt inhibition potentiate apoptosis of breast cancer cells in vitro and suppress tumor growth in vivo,” by researchers from Kent State University, Kent, Ohio, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Abstract:
Targeted drug approaches have been a major focus for developing new anticancer therapies. Although many such agents approved in the last 20 years have improved outcomes, almost all have underperformed expectations. The full potential of such agents may yet be obtained through novel combinations. Previously, we showed that anti-estrogen drugs combined with a dendritic cell-based anti-HER-2 vaccine known to induce strong Th1-polarized immunity dramatically improved clinical response rates in patients with HER-2pos/ERpos early breast cancer. Here, we show that the small molecule Akt antagonist MK-2206, when combined with the Th1 cytokines IFN-gamma and TNF-alpha, maximize indicators of apoptotic cell death in a panel of phenotypically-diverse human breast cancer lines. These findings were mirrored by other, structurally-unrelated Akt-targeting drugs that work through different mechanisms. Interestingly, we found that MK-2206, as well as the other Akt antagonist drugs, also had a tendency to suppress Th1 cytokine expression in stimulated human and murine lymphocytes, potentially complicating their use in conjunction with active immunotherapy. After verifying that MK-2206 plus IFN-gamma could show similar combined effects against breast cancer lines, even in the absence of TNF-alpha, we tested in a rodent HER-2pos breast cancer model either a HER-2-based DC vaccine, or recombinant IFN-gamma with or without MK-2206 administration. We found that for MK-2206, co-administration of recombinant IFN-gamma outperformed co-administration of DC vaccination for slowing tumor growth kinetics. These findings suggest a combined therapy approach for Akt-targeting drugs that incorporates recombinant Interferon-gamma and is potentially translatable to humans.

Press release - https://www.oncotarget.com/news/pr/th1-cytokines-potentiate-apoptosis-of-breast-cancer-cells-and-suppress-tumor-growth/

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DOI - https://doi.org/10.18632/oncotarget.27556

Full text - https://www.oncotarget.com/article/27556/text/

Correspondence to - Gary K. Koski - dendritic_cell@hotmail.com

Keywords - breast cancer, Akt kinase, immunotherapy

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