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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Li, Z; Razavi, P; Li, Q; Toy, W; Liu, B; Ping, C; Hsieh, W; Sanchez-Vega, F; Brown, DN; Da Cruz Paula, AF; Morris, L; Selenica, P; Eichenberger, E; Shen, R; Schultz, N; Rosen, N; Scaltriti, M; Brogi, E; Baselga, J; Reis-Filho, JS; Chandarlapaty, S

Published Date

  • December 2018

Published In

Volume / Issue

  • 34 / 6

Start / End Page

  • 893 - 905.e8

PubMed ID

  • 30537512

Pubmed Central ID

  • PMC6294301

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

International Standard Serial Number (ISSN)

  • 1535-6108

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2018.11.006

Language

  • eng