TY - JOUR
T1 - Rationally derived drug combinations with the novel Mcl-1 inhibitor EU-5346 in breast cancer
AU - Vallet, Sonia
AU - Fan, Fengjuan
AU - Malvestiti, Stefano
AU - Pecherstorfer, Martin
AU - Sattler, Martin
AU - Schneeweiss, Andreas
AU - Schulze-Bergkamen, Henning
AU - Opferman, Joseph T
AU - Cardone, Michael H
AU - Jäger, Dirk
AU - Podar, Klaus
N1 - Funding Information:
SM is the recipient of a DGHO/ Jose Carreras stipend. KP is the recipient of a B. Braun Stiftungs Grant. MP and KP received research support from Roche Pharmaceuticals. We cordially thank Muhammad Hasan Bashari for technical assistance.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/2/15
Y1 - 2019/2/15
N2 - 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.
AB - 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.
KW - Antineoplastic Agents/adverse effects
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Breast Neoplasms/diagnosis
KW - Cardiotoxicity
KW - Cell Line, Tumor
KW - Dose-Response Relationship, Drug
KW - Drug Combinations
KW - Female
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Inhibitory Concentration 50
KW - Molecular Targeted Therapy
KW - Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors
KW - Proto-Oncogene Proteins c-bcl-2/genetics
KW - bcl-X Protein/genetics
UR - http://www.scopus.com/inward/record.url?scp=85055982251&partnerID=8YFLogxK
U2 - 10.1007/s10549-018-5022-5
DO - 10.1007/s10549-018-5022-5
M3 - Journal article
C2 - 30374681
SN - 0167-6806
VL - 173
SP - 585
EP - 596
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -