Related Experiment Video

Updated: May 27, 2025

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
07:16

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

Published on: September 13, 2018

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Cooperation between the Hippo and MAPK pathway activation drives acquired resistance to TEAD inhibition

Sayantanee Paul1, Thijs J Hagenbeek1, Julien Tremblay2

  • 1Department of Discovery Oncology, Genentech Inc, South San Francisco, CA, USA.

Nature Communications
|February 18, 2025
PubMed

Insights

Resistance to TEAD inhibitors in cancer emerges due to increased AP-1 (activator protein-1) activity and restored YAP (yes-associated protein)-TEAD binding. MAPK pathway inhibitors may overcome this resistance in Hippo pathway-dependent cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • TEAD (transcriptional enhanced associate domain) transcription factors are key effectors of the Hippo pathway in cancer.
  • Resistance to targeted therapies, including TEAD inhibitors, is a significant clinical challenge.
  • Mechanisms of resistance to TEAD inhibition are not fully understood.

Purpose of the Study:

  • To investigate the mechanisms driving resistance to TEAD inhibition.
  • To explore the interplay between the Hippo and MAPK pathways in cancer drug resistance.
  • To identify potential strategies for overcoming TEAD inhibitor resistance.

Main Methods:

  • Utilized a pan-TEAD inhibitor (GNE-7883) in cancer models.
  • Assessed YAP-TEAD binding and transcriptional activity.
  • Analyzed chromatin occupancy and pathway activity (MAPK, AP-1).
  • Investigated the role of FOSL1 in TEAD inhibitor resistance.

Main Results:

  • Upregulation of AP-1 (activator protein-1) transcription factors and restored YAP (yes-associated protein)-TEAD activity drive resistance to GNE-7883.
  • Resistant cells show restored YAP and TEAD chromatin binding and increased MAPK pathway activity.
  • FOSL1 is essential for YAP and TEAD chromatin binding and contributes to resistance.

Conclusions:

  • A clinically relevant interplay exists between the Hippo and MAPK pathways in the context of TEAD inhibitor resistance.
  • Restored AP-1 activity and enhanced MAPK signaling are key mechanisms of resistance.
  • MAPK pathway inhibitors show promise in mitigating resistance to TEAD inhibition in relevant cancers.

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