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Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer
Authors:Thomas D. Wright  Christopher Raybuck  Akshita Bhatt  Darlene Monlish  Suravi Chakrabarty  Katy Wendekier  Nathan Gartland  Mohit Gupta  Matthew E. Burow  Patrick T. Flaherty  Jane E. Cavanaugh
Affiliation:1. Department of Pharmacology and Toxicology, Duquesne University, Pittsburgh, Pennsylvania;2. Department of Pharmacology and Toxicology, Duquesne University, Pittsburgh, Pennsylvania

Department of Pediatrics, Washington University in St Louis, St Louis, Missouri;3. Department of Medicinal Chemistry, Duquesne University, Pittsburgh, Pennsylvania

Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium;4. Department of Medicinal Chemistry, Duquesne University, Pittsburgh, Pennsylvania;5. Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana

Abstract:Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.
Keywords:MEK5/ERK5  PI3K/Akt  synergy  triple-negative breast cancer
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