Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway Journal Article

Authors: Li, Z.; Razavi, P.; Li, Q.; Toy, W.; Liu, B.; Ping, C.; Hsieh, W.; Sanchez-Vega, F.; Brown, D. N.; Da Cruz Paula, A. F.; Morris, L.; Selenica, P.; Eichenberger, E.; Shen, R.; Schultz, N.; Rosen, N.; Scaltriti, M.; Brogi, E.; Baselga, J.; Reis-Filho, J. S.; Chandarlapaty, S.
Article Title: Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway
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. Li et al. identify inactivation of RB1 and FAT1 to be associated with resistance of ER+ breast cancer to CDK4/6 inhibitors (CDK4/6i). FAT1 loss increases CDK6 expression via the Hippo pathway. Inactivation of the Hippo pathway component NF2 also increases CDK6 expression and reduces sensitivity to CDK4/6i. © 2018 Elsevier Inc.
Keywords: protein expression; unclassified drug; promoter region; somatic mutation; missense mutation; outcome assessment; protein function; protein localization; progression free survival; breast cancer; gene expression; transcription factor; drug resistance; cancer resistance; tumor suppressor gene; messenger rna; gene loss; tumor growth; cyclin dependent kinase inhibitor; cell cycle regulation; transcription factor yap1; cyclin dependent kinase 4; cyclin dependent kinase 6; hippo pathway; copy number variation; yap; genetic resistance; rb1; estrogen receptor positive breast cancer; fat1; human; priority journal; article; palbociclib; hippo signaling; abemaciclib; ribociclib; positron emission tomography-computed tomography; cdk4/6 inhibitors; transcription factor taz; tumor suppressor gene fat1
Journal Title: Cancer Cell
Volume: 34
Issue: 6
ISSN: 1535-6108
Publisher: Cell Press  
Date Published: 2018-12-10
Start Page: 893
End Page: 905.e8
Language: English
DOI: 10.1016/j.ccell.2018.11.006
PROVIDER: scopus
PMCID: PMC6294301
PUBMED: 30537512
Notes: Cancer Cell -- Export Date: 2 January 2019 -- Article -- CODEN: CCAEC C2 - 30537512 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Neal Rosen
    351 Rosen
  2. Ronglai Shen
    126 Shen
  3. Luc Morris
    122 Morris
  4. Edi Brogi
    303 Brogi
  5. Nikolaus D Schultz
    193 Schultz
  6. Weiyi Toy
    13 Toy
  7. Zhiqiang Li
    7 Li
  8. Jorge Sergio Reis
    283 Reis
  9. Jose T Baselga
    389 Baselga
  10. Pedram Razavi
    23 Razavi
  11. Bo Liu
    3 Liu
  12. QING LI
    2 LI
  13. David Norman Brown
    3 Brown
  14. Christina Ping
    1 Ping
  15. Wilson Hsieh
    1 Hsieh