ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins.

Abstract

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

• Authors: Clara Alcon, Jorge Gómez Tejeda Zañudo, Reka Albert, Nikhil Wagle, Maurizio Scaltriti, Anthony Letai, Josep Samitier, Joan Montero
• Journal: Cells (Cells) Vol. 10 Issue 7 (07 02 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34359829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• BCL2L1 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• ESR1 protein, human
• Estrogen Receptor alpha
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Piperazines
• Protein Isoforms
• Pyridines
• Pyrimidines
• S63845
• Sulfonamides
• Thiazoles
• Thiophenes
• bcl-X Protein
• Alpelisib
• Fulvestrant
• ipatasertib
• Everolimus
• Proto-Oncogene Proteins c-akt
• palbociclib
• venetoclax

Topics

• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Estrogen Receptor alpha (genetics, metabolism)
• Everolimus (pharmacology)
• Female
• Fulvestrant (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, metabolism)
• Piperazines (pharmacology)
• Protein Isoforms (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction
• Sulfonamides (pharmacology)
• Thiazoles (pharmacology)
• Thiophenes (pharmacology)
• bcl-X Protein (antagonists & inhibitors, genetics, metabolism)