AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution

• Published in: Nature (London) Vol. 635; no. 8039; pp. 755 - 763
• Main Authors: Schade, Amy E., Perurena, Naiara, Yang, Yoona, Rodriguez, Carrie L., Krishnan, Anjana, Gardner, Alycia, Loi, Patrick, Xu, Yilin, Nguyen, Van T. M., Mastellone, G. M., Pilla, Natalie F., Watanabe, Marina, Ota, Keiichi, Davis, Rachel A., Mattioli, Kaia, Xiang, Dongxi, Zoeller, Jason J., Lin, Jia-Ren, Morganti, Stefania, Garrido-Castro, Ana C., Tolaney, Sara M., Li, Zhe, Barbie, David A., Sorger, Peter K., Helin, Kristian, Santagata, Sandro, Knott, Simon R. V., Cichowski, Karen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.11.2024; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/106; 13/2; 13/51; 13/89; 13/95; 14/63; 38/39; 38/90; 631/67/1059/602; 631/67/1347; 631/67/395; AKT protein; AKT1 protein; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast cancer; Cancer therapies; Cell culture; Cell death; Cell Death - drug effects; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Deregulation; Drug Synergism; Drug Therapy, Combination; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenetics; Female; Genes; Histone methyltransferase; Humanities and Social Sciences; Humans; Immunotherapy; Inhibitors; Machine Learning; Mammary gland; Mammary glands; Mice; multidisciplinary; Mutation; Organ Specificity; Pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Regression analysis; Science; Science (multidisciplinary); Stem cells; Synergism; Therapeutic targets; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08031-6

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence 1 . The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived 1 , 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 PTEN 3 – 6 . However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors 7 . 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. AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple triple-negative breast cancer models in vivo by triggering an involution-like process.