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

Sonia Vallet, Fengjuan Fan, Stefano Malvestiti, Martin Pecherstorfer, Martin Sattler, Andreas Schneeweiss, Henning Schulze-Bergkamen, Joseph T Opferman, Michael H Cardone, Dirk Jäger, Klaus Podar

Research output: Journal article (peer-reviewed)Journal article

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)585-596
Number of pages12
JournalBreast Cancer Research and Treatment
Volume173
Issue number3
DOIs
Publication statusPublished - 15 Feb 2019

Keywords

  • Antineoplastic Agents/adverse effects
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Breast Neoplasms/diagnosis
  • Cardiotoxicity
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Female
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Inhibitory Concentration 50
  • Molecular Targeted Therapy
  • Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2/genetics
  • bcl-X Protein/genetics

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