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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

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The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells

Giulia Gobbi1, Benedetta Donati1, Italo Faria Do Valle2

  • 1Laboratory of Translational Research, Azienda USL di Reggio Emilia - IRCCS, Reggio Emilia, Italy.

Oncogene
|August 14, 2019
PubMed

Insights

BET inhibitors (BETi) show promise for lung cancer, but resistance mechanisms are unknown. Hippo pathway genes (LATS2, TAOK1, NF2) and TAZ/YAP activity determine sensitivity, offering potential biomarkers for BETi therapy in non-small cell lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Bromodomain and Extra-Terminal domain (BET) inhibitors (BETi) are emerging anti-cancer drugs with clinical trials for non-small cell lung cancer (NSCLC).
  • Currently, no predictive biomarkers exist to identify patients likely to respond to BETi therapy.
  • Understanding resistance mechanisms is crucial for optimizing BETi efficacy.

Purpose of the Study:

  • To identify mechanisms of resistance to BET inhibitors in lung cancer.
  • To uncover potential predictive biomarkers for BETi treatment response.

Main Methods:

  • Genome-scale CRISPR/Cas9 screening was performed in lung cancer cells to identify resistance mechanisms.
  • Gene expression and localization of key proteins were analyzed.
  • Molecular alterations in NSCLC patient cohorts were assessed.

Main Results:

  • Three Hippo pathway genes (LATS2, TAOK1, NF2) were identified as key determinants of sensitivity to BETi.
  • Knockout of these genes conferred resistance to BETi by promoting TAZ nuclear localization and activity.
  • TAZ, YAP, and TEAD were identified as direct targets of BRD4, with BETi treatment downregulating their expression.
  • Alterations in these genes are frequent in NSCLC, and TAZ amplification/overexpression correlates with poor outcomes in lung adenocarcinoma.

Conclusions:

  • The Hippo pathway plays a central role in mediating resistance to BET inhibitors.
  • BETi can counteract pro-oncogenic YAP/TAZ activity.
  • Hippo pathway components and TAZ/YAP activity are potential predictive biomarkers for BETi therapy in NSCLC.

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