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

  • Breast Cancer Res Treat. 2019 Feb;173(3):585-596. doi: 10.1007/s10549-018-5022-5.
Sonia Vallet  1  2 ,  Fengjuan Fan  1  3 ,  Stefano Malvestiti  1 ,  Martin Pecherstorfer  2 ,  Martin Sattler  4  5 ,  Andreas Schneeweiss  1 ,  Henning Schulze-Bergkamen  1 ,  Joseph T Opferman  6 ,  Michael H Cardone  7 ,  Dirk Jäger  1  8 ,  Klaus Podar  9  10
Affiliations
  • 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. [email protected].
  • 10. Department of Internal Medicine II, University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria. [email protected].
PMID: 30374681 DOI: 10.1007/s10549-018-5022-5
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.
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