AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution

• 成果类型: Article
• 署名作者: 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
• 署名单位: Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Cedars Sinai Medical Center; Cedars Sinai Medical Center; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of London; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3783
• DOI: 10.1038/s41586-024-08031-6
• 发表日期: 2024-11-21
• 页码: 755-+
• 关键词: mammary-gland morphogenesis; breast-cancer; activated akt; expression; mutations; pten; transcription; landscape; maintains; alpelisib

摘要

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 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 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.