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. Epub 2018 Oct 29.


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.

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • 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
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism


  • Antineoplastic Agents
  • BCL2 protein, human
  • Drug Combinations
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein