Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway
Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway
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DOI：
10.1016/j.ccell.2018.11.006
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发表时间：
2018-12-10
期刊：
影响因子：
50.3
通讯作者：
Chandarlapaty, Sarat
中科院分区：
文献类型：
--
作者：
Li, Zhiqiang;Razavi, Pedram;Chandarlapaty, Sarat
细胞周期蛋白依赖性激酶4/6 （CDK4/6）抑制剂（CDK4/6i）对乳腺癌有效；然而，耐药性是经常遇到的问题，但人们对其了解甚少。我们对348例接受CDK4/6i治疗的雌激素受体阳性（ER+）乳腺癌进行了基因组分析，并确定了影响FAT1和RB1的功能丧失突变与耐药性有关。FAT1缺失导致CDK6显著升高，抑制CDK6可恢复对CDK4/6i的敏感性。CDK6的诱导是通过Hippo途径介导的，在CDK6启动子上积累了YAP和TAZ转录因子。其他Hippo通路组分的基因组改变也被发现可促进CDK4/6i耐药性。这些发现揭示了Hippo信号在ER+乳腺癌中的肿瘤抑制功能，并建立了FAT1丢失作为CDK4/6i耐药的机制。
Cyclin dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) are effective in breast cancer; however, drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 348 estrogen receptor-positive (ER+) breast cancers treated with CDK4/6i and identified loss-of-function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6, the suppression of which restored sensitivity to CDK4/6i. The induction of CDK6 was mediated by the Hippo pathway with accumulation of YAP and TAZ transcription factors on the CDK6 promoter. Genomic alterations in other Hippo pathway components were also found to promote CDK4/6i resistance. These findings uncover a tumor suppressor function of Hippo signaling in ER+ breast cancer and establish FAT1 loss as a mechanism of resistance to CDK4/6i.