Posted January 19, 2022

Carl Maki, Ph.D., Rush University Medical Center

Triple negative breast cancer (TNBC) is an aggressive type of cancer with limited treatment options and poor prognosis, resulting in an urgent need for new forms of treatment. One enzyme that represents a potential therapeutic target for TNBC is called prolyl endopeptidase (PREP), an enzyme expressed at high levels in multiple cancers including breast cancer. Previous studies have provided evidence that PREP plays an important role in cancer cell proliferation and survival, suggesting PREP inhibitors could have potential as a treatment option for cancer. With Breast Cancer Research Stamp support, Dr. Carl Maki and his team investigated the effects of a PREP inhibitor, Y-29794, on TNBC cell lines and mouse models with the hopes of identifying a novel therapeutic for this aggressive breast cancer subtype.

The research team first confirmed through in vitro studies that Y-29794 inhibits the endopeptidase activity of PREP in TNBC cells. In addition, Y-29794 was shown to inhibit the survival and proliferation of multiple TNBC cell lines. At low doses, Y-29794 slowed cell cycle progression in TNBC cells, whereas high doses induced cell death. Dr. Maki and his team next investigated the effects of Y-29794 on the IRS1-AKT-mTORC1 survival and growth signaling pathway, which is often upregulated in TNBC. Y-29794 was shown to cause a decrease in Insulin Receptor Substrate 1 (IRS1) protein levels, a reduction in activated AKT protein, and a decrease in the mechanistic target of rapamycin complex 1 (mTORC1) protein activity. These findings suggest that IRS1-AKT-mTORC1 is one pathway through which Y-29794 likely inhibits TNBC cell survival and proliferation. Interestingly, depletion of PREP alone was not sufficient to inhibit the IRS1-AKT-mTORC1 pathway or reduce cell proliferation or survival, suggesting that Y-29794 targets other proteins in addition to PREP to elicit its effects in TNBC cells.

To examine the effects of treatment with Y-29794 on tumor growth in vivo, Dr. Maki and his team performed studies with mouse models of TNBC. Importantly, the team demonstrated that in mouse models, treatment with Y-29794 caused a significant reduction in TNBC tumor growth. Taken together, the findings from Dr. Maki's in vitro and in vivo research support the possibility that Y-29794, or a compound with similar mode of action, may be an effective treatment option for TNBC.

Publication:

Perez RE, Calhoun S, Shim D, et al. 2020. Prolyl endopeptidase inhibitor Y-29794 blocks the IRS1-AKT-mTORC1 pathway and inhibits survival and in vivo tumor growth of triple-negative breast cancer. Cancer Biol Ther 21(11):1033-1040.

Link:

Public and Technical Abstracts:  Targeting Prolyl Peptidases in Triple-Negative Breast Cancer

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