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

Cancer Cell. 2018 Dec 10;34(6):893-905.e8. doi: 10.1016/j.ccell.2018.11.006.

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.

Keywords: CDK4/6 inhibitors; FAT1; Hippo pathway; RB1; YAP; abemaciclib; breast cancer; drug resistance; palbociclib; ribociclib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • HEK293 Cells
  • Hippo Signaling Pathway
  • Humans
  • Loss of Function Mutation
  • MCF-7 Cells
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays*

Substances

  • Cadherins
  • FAT1 protein, human
  • Protein Kinase Inhibitors
  • Tumor Suppressor Proteins
  • Protein Serine-Threonine Kinases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6