Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway

被引：373

作者：

Li, Zhiqiang ^{[1
]}

Razavi, Pedram ^{[1
,2
,3
]}

Li, Qing ^{[1
]}

Toy, Weiyi ^{[1
]}

Liu, Bo ^{[1
]}

Ping, Christina ^{[2
]}

Hsieh, Wilson ^{[1
]}

Sanchez-Vega, Francisco ^{[1
]}

Brown, David N. ^{[4
]}

Paula, Arnaud F. Da Cruz ^{[4
]}

Morris, Luc ^{[1
]}

Selenica, Pier ^{[3
]}

Eichenberger, Emily ^{[3
]}

Shen, Ronglai ^{[5
]}

Schultz, Nikolaus ^{[1
]}

Rosen, Neal ^{[2
,3
]}

Scaltriti, Maurizio ^{[1
,4
]}

Brogi, Edi ^{[4
]}

Baselga, Jose ^{[1
,2
,6
]}

Reis-Filho, Jorge S. ^{[4
]}

Chandarlapaty, Sarat ^{[1
,2
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] MSKCC, Breast Med Serv, Dept Med, New York, NY 10065 USA

[3] Weill Cornell Med Coll, New York, NY 10065 USA

[4] MSKCC, Dept Pathol, New York, NY 10065 USA

[5] MSKCC, Dept Epidemiol & Biostat, New York, NY 10065 USA

[6] Vall dHebron Inst Oncol, Barcelona, Spain

来源：

CANCER CELL | 2018年 / 34卷 / 06期

关键词：

BREAST-CANCER; MUTATIONAL LANDSCAPE; CADHERIN ACTS; GENE; ABEMACICLIB; PALBOCICLIB; DROSOPHILA; UPSTREAM; GROWTH; TAZ;

D O I：

10.1016/j.ccell.2018.11.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：893 / +

页数：21

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