Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway

Cancer Cell. 2020 Jan 13;37(1):104-122.e12. doi: 10.1016/j.ccell.2019.12.006.

Abstract

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.

Keywords: YAP; dormancy; drug resistance; drug tolerance; epidermal growth factor receptor; lung cancer; senescence.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cellular Senescence
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • MAP Kinase Kinase 1 / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Yap1 protein, mouse
  • EGFR protein, human
  • ErbB Receptors
  • MAP Kinase Kinase 1