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Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM

Kyung-A Song1, Matthew J Niederst2,3, Timothy L Lochmann1

  • 1Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Richmond, Virginia.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|October 21, 2017
PubMed

Insights

Epithelial-to-mesenchymal transition (EMT) causes resistance to lung cancer therapies by ZEB1 blocking BIM expression. Restoring BIM sensitizes cancers to EGFR inhibitors, revealing a new resistance mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epithelial-to-mesenchymal transition (EMT) is a known mechanism of resistance to cancer therapies.
  • The precise mechanisms by which EMT confers resistance, particularly to targeted therapies like EGFR inhibitors (EGFRi), remain incompletely understood.
  • Understanding this link is crucial for developing strategies to overcome therapeutic resistance in lung cancer.

Purpose of the Study:

  • To investigate the underlying mechanisms of EMT-mediated resistance to EGFR inhibitors in EGFR-mutant lung cancers.
  • To identify specific molecular players involved in this resistance pathway.
  • To explore potential therapeutic strategies to re-sensitize resistant tumors.

Main Methods:

  • Development of multiple models of EMT-mediated resistance to EGFR inhibitors in EGFR-mutant lung cancer cell lines.
  • Analysis of BIM expression levels in mesenchymal versus epithelial lung cancer cells.
  • Investigation of the role of the EMT transcription factor ZEB1 in regulating BIM expression via promoter binding assays.
  • Assessment of tumor response to EGFR inhibitors following ZEB1 depletion or BH3 mimetic treatment (ABT-263).
  • Validation of findings in KRAS-mutant lung cancers and large cancer datasets.

Main Results:

  • Mesenchymal EGFR-mutant lung cancers exhibit resistance to EGFR inhibitors due to insufficient BIM expression, preventing apoptosis despite suppressed oncogenic signaling.
  • The EMT transcription factor ZEB1 directly binds to the BIM promoter, inhibiting its transcription.
  • Depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 restored BIM expression and re-sensitized resistant lung cancers to EGFR inhibitors.
  • The observed link between EMT, ZEB1, and BIM was conserved across different lung cancer subtypes and other cancer types.

Conclusions:

  • A novel mechanism linking EMT to resistance against targeted lung cancer therapies is elucidated.
  • ZEB1-mediated suppression of BIM is identified as a key driver of resistance to EGFR inhibitors in EMT-phenotype lung cancers.
  • Targeting the BIM pathway or ZEB1 offers a potential strategy to overcome EMT-driven therapeutic resistance in lung cancer.

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