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Breast Cancer Res Treat. 2019 Feb;173(3):585-596. doi: 10.1007/s10549-018-5022-5. Epub 2018 Oct 29.

Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer.

Author information

1
Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany.
2
Department of Internal Medicine II, University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria.
3
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
5
Department of Medicine, Harvard Medical School, Boston, MA, USA.
6
St. Jude Children's Research Hospital, Memphis, TN, USA.
7
Eutropics Pharmaceuticals, Inc., Cambridge, MA, USA.
8
German Cancer Research Center (DKFZ), Applied Tumor Immunity, Heidelberg, Germany.
9
Department of Medical Oncology, National Center for Tumor Diseases (NCT), University of Heidelberg, Heidelberg, Germany. klaus.podar@krems.lknoe.at.
10
Department of Internal Medicine II, University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria. klaus.podar@krems.lknoe.at.

Abstract

PURPOSE:

Recent studies have emphasized a key role for the anti-apoptotic Bcl-2 family member Mcl-1 in conferring tumor cell survival and drug resistance in breast cancer (BC). Mcl-1 inhibitors, such as the BH3-mimetic EU-5346, therefore represent an exciting new class of targeting agents and are a current focus of widespread cancer-drug development efforts.

METHODS:

ONCOMINE analysis was utilized to compare expression profiles of Bcl-2 family members across all major BC subgroups. Potential toxicities of EU-5346 were evaluated using iPS-generated cardiomyocytes, blood cells and astrocytes. The anti-BC cell activity of EU-5346-based therapies was evaluated using [3H]-thymidine uptake and spheroid-forming assays as well as immunoblotting and the Chou-Talalay method. Protein level-based activity of EU-5346, the specific anti-Bcl-2 inhibitor ABT-199 and the specific anti-Bcl-xL inhibitor WEHI-539 was verified in Mcl-1Δ/null versus Mcl-1wt/wt MEFs.

RESULTS:

We previously demonstrated significant anti-tumor activity of EU-5346 in all BC subtypes. Our present results go further and suggest that EU-5346 may induce limited adverse events such as cardiotoxicity, hematotoxicity, and neurotoxicity, frequently observed with other BH3 mimetics. As demonstrated by our mathematical scoring model, the prediction of EU-5643-induced IC50 not only relies on the protein level of Mcl-1 but also on Bak, Bim, and Noxa. Synergistic anti-BC activity of low-dose EU-5346 with the BH3 mimetics ABT-199 or WEHI-539 was observed only in those BC cells expressing Bcl-2 or Bcl-xL, respectively. Similarly, when combined with tamoxifen or trastuzumab, low-dose EU-5346 induced significant anti-BC activity in hormone receptor positive or Her2-positive BC cells, respectively. Finally, EU-5346 in combination with paclitaxel induced synergistic anti-BC activity in both paclitaxel-sensitive and paclitaxel-resistant TNBC cells.

CONCLUSION:

These data strongly support the further clinical development of EU-5346 to improve BC patient survival.

KEYWORDS:

BH3 mimetics; Breast cancer; Combination therapies; Mathematical scoring model; Mcl-1

PMID:
30374681
DOI:
10.1007/s10549-018-5022-5
[Indexed for MEDLINE]

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