三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对常规的内分泌治疗和HER2靶向治疗基本无效，与乳腺癌亚型相比，侵袭性最强、复发率最高。晚期三阴性乳腺癌已经发生远处转移，失去手术和放疗等局部治疗机会，目前主要依靠全身化疗±免疫治疗，但是疗效通常十分短暂，因此迫切需要研发更有效的治疗方法。AKT是重要的致癌基因，分别受到PIK3CA和PTEN基因的激活和抑制作用，大约50%的乳腺癌存在PIK3CA、AKT1激活或者PTEN失活，三阴性乳腺癌更是超过70%，从而成为合理的治疗靶点，但是既往研究发现AKT抑制剂仅对激素受体阳性乳腺癌疗效显著，对三阴性乳腺癌疗效反而不佳。
　　2024年10月9日，全球自然科学三大旗舰期刊之首、创刊155年的英国《自然》正刊在线发表美国哈佛大学医学院、布莱根医院和波士顿妇女医院、达娜法伯癌症研究院、西达赛奈医学中心（雪松西奈医疗中心）塞缪尔奥斯钦综合癌症研究院、英国伦敦大学癌症研究院的研究报告，首次发现AKT抑制剂联合组蛋白甲基转移酶EZH2抑制剂通过劫持退化机制可杀死三阴性乳腺癌，成为大有希望的治疗组合。
　　多种三阴性乳腺癌动物模型体内实验表明，AKT抑制剂与EZH2抑制剂具有协同作用，并可强有力地促进肿瘤消失。
　　机制分析发现，AKT抑制剂和EZH2抑制剂首先通过协同驱动基底样三阴性乳腺癌细胞进入分化程度更高的激素受体阳性状态发挥上述作用，而单用其中任何一种药物都无法有效诱导该状态。三阴性乳腺癌一旦分化，就被这些药物通过劫持触发乳腺退化的信号杀死。
　　利用人工智能机器学习方法，该研究还研发出可用于预测两种抑制剂联合治疗敏感性的分类方法，有助于进一步筛选患者进行精准治疗。
　　因此，该研究结果为三阴性乳腺癌这种高度侵袭性肿瘤类型确定了令人鼓舞的治疗策略，并且阐明了表观遗传酶EZH2失调如何使肿瘤免受致癌靶点的影响。该研究还揭示了如何利用乳腺组织特异性细胞死亡信号传导通路取得治疗获益，故有必要进一步开展临床研究进行验证。

Nature. 2024 Oct 9. IF: 50.5
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, Van T. M. Nguyen, 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, Karen Cichowski.
Harvard Medical School, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA; Cedars-Sinai Medical Center, Los Angeles, CA, USA; Institute of Cancer Research, London, UK.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived. 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. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors. 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.
DOI: 10.1038/s41586-024-08031-6