| Literature DB >> 30537512 |
Zhiqiang Li1, Pedram Razavi2, Qing Li1, Weiyi Toy1, Bo Liu1, Christina Ping3, Wilson Hsieh1, Francisco Sanchez-Vega1, David N Brown4, Arnaud F Da Cruz Paula4, Luc Morris1, Pier Selenica5, Emily Eichenberger5, Ronglai Shen6, Nikolaus Schultz1, Neal Rosen7, Maurizio Scaltriti8, Edi Brogi4, Jose Baselga9, Jorge S Reis-Filho4, Sarat Chandarlapaty10.
Abstract
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.Entities:
Keywords: CDK4/6 inhibitors; FAT1; Hippo pathway; RB1; YAP; abemaciclib; breast cancer; drug resistance; palbociclib; ribociclib
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Year: 2018 PMID： 30537512 PMCID： PMC6294301 DOI： 10.1016/j.ccell.2018.11.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743