美国布莱根妇女医院Karen Cichowski团队近期取得重要工作进展，他们研究提出，AKT和EZH2抑制剂通过劫持癌变机制杀死三阴性乳腺癌（TNBC）细胞。相关研究成果2024年10月9日在线发表于《自然》杂志上。

据介绍，三阴性乳腺癌（TNBC）是最具侵袭性的癌症亚型，复发率最高。晚期TNBC的主要护理标准是全身化疗加或不加免疫治疗；然而，反应通常是短暂的。因此，迫切需要开发更有效的治疗方法。PI3K通路的组成部分代表了可能的治疗靶点；超过70%的TNBC具有PIK3CA、AKT1或PTEN的改变。然而，与激素受体阳性肿瘤相比，目前尚不清楚三阴性疾病是否或如何对PI3K通路抑制剂产生反应。

研究人员描述了一种有前景的基于AKT抑制剂的TNBC治疗组合。研究人员表明AKT抑制剂与抑制组蛋白甲基转移酶EZH2的药物协同作用，并在体内多种TNBC模型中促进肿瘤的稳健消退。

AKT和EZH2抑制剂通过首先协同驱动基底样TNBC细胞，进入更分化的管腔样状态来发挥这些作用，而单独使用任何一种药物都无法有效诱导这种状态。一旦TNBC被分化，这些药物就会通过劫持通常驱动乳腺退化的信号来杀死它们。使用机器学习方法，研究人员开发了一个可用于预测灵敏度的分类器。

总之，这一研究为高度侵袭性的肿瘤类型确定了一种有前景的治疗策略，并说明了表观遗传酶的失调如何使肿瘤免受致癌易感性的影响。这一研究结果还揭示了，如何利用发育中的组织特异性细胞死亡途径来获得治疗益处。

附：英文原文

Title: AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution

Author: 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

Issue&Volume: 2024-10-09

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 PTEN3,4,5,6. 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.

DOI: 10.1038/s41586-024-08031-6

Source: https://www.nature.com/articles/s41586-024-08031-6