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Article

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

1
Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
2
Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
3
Department of Biology, The Pennsylvania State University, University Park, PA 16802-6300, USA
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
5
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
6
Department of Electronics and Biomedical Engineering, University of Barcelona (UB), 08028 Barcelona, Spain
7
Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Present address: AstraZeneca, Gaithersburg, MD 20878, USA.
Academic Editor: Paolo Bernardi
Cells 2021, 10(7), 1659; https://doi.org/10.3390/cells10071659
Received: 31 May 2021 / Revised: 18 June 2021 / Accepted: 28 June 2021 / Published: 2 July 2021
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. View Full-Text
Keywords: ER+ breast cancer; DBP; priming; apoptosis; targeted therapies; resistance; BH3 mimetics ER+ breast cancer; DBP; priming; apoptosis; targeted therapies; resistance; BH3 mimetics
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MDPI and ACS Style

Alcon, C.; Gómez Tejeda Zañudo, J.; Albert, R.; Wagle, N.; Scaltriti, M.; Letai, A.; Samitier, J.; Montero, J. ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins. Cells 2021, 10, 1659. https://doi.org/10.3390/cells10071659

AMA Style

Alcon C, Gómez Tejeda Zañudo J, Albert R, Wagle N, Scaltriti M, Letai A, Samitier J, Montero J. ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins. Cells. 2021; 10(7):1659. https://doi.org/10.3390/cells10071659

Chicago/Turabian Style

Alcon, Clara, Jorge Gómez Tejeda Zañudo, Reka Albert, Nikhil Wagle, Maurizio Scaltriti, Anthony Letai, Josep Samitier, and Joan Montero. 2021. "ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins" Cells 10, no. 7: 1659. https://doi.org/10.3390/cells10071659

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