AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution

Amy E. Schade, Naiara Perurena, Yoona Yang, Carrie L. Rodriguez, Anjana Krishnan, Alycia Gardner, Patrick Loi, Yilin Xu, Nguyen Van T. M., G. M. Mastellone, Natalie F. Pilla, Marina Watanabe, Keiichi Ota, Rachel A. Davis, Kaia Mattioli, Dongxi Xiang, Jason J. Zoeller, Jia-Ren Lin, Stefania Morganti, Ana C. Garrido-Castro, Sara M. Tolaney, Zhe Li, David A. Barbie, Peter K. Sorger, Kristian Helin, Sandro Santagata, Simon R. V. Knott and Karen Cichowski ()
Additional contact information
Amy E. Schade: Brigham and Women’s Hospital
Naiara Perurena: Brigham and Women’s Hospital
Yoona Yang: Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute
Carrie L. Rodriguez: Brigham and Women’s Hospital
Anjana Krishnan: Brigham and Women’s Hospital
Alycia Gardner: Brigham and Women’s Hospital
Patrick Loi: Brigham and Women’s Hospital
Yilin Xu: Harvard Medical School
Nguyen Van T. M.: Institute of Cancer Research
G. M. Mastellone: Brigham and Women’s Hospital
Natalie F. Pilla: Brigham and Women’s Hospital
Marina Watanabe: Brigham and Women’s Hospital
Keiichi Ota: Dana-Farber Cancer Institute
Rachel A. Davis: Brigham and Women’s Hospital
Kaia Mattioli: Brigham and Women’s Hospital
Dongxi Xiang: Brigham and Women’s Hospital
Jason J. Zoeller: Harvard Medical School
Jia-Ren Lin: Harvard Medical School
Stefania Morganti: Harvard Medical School
Ana C. Garrido-Castro: Harvard Medical School
Sara M. Tolaney: Harvard Medical School
Zhe Li: Brigham and Women’s Hospital
David A. Barbie: Dana-Farber Cancer Institute
Peter K. Sorger: Harvard Medical School
Kristian Helin: Institute of Cancer Research
Sandro Santagata: Harvard Medical School
Simon R. V. Knott: Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute
Karen Cichowski: Brigham and Women’s Hospital

Nature, 2024, vol. 635, issue 8039, 755-763

Abstract: Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3–6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

Date: 2024
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DOI: 10.1038/s41586-024-08031-6

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