YAP-TEAD inhibition is associated with upregulation of an androgen receptor mediated transcription program providing

Related Experiment Video

Updated: Jun 12, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

6.8K

Roberto Alva-Ruiz1, Ryan D Watkins1, Jennifer L Tomlinson1

  • 1Division of Hepatobiliary & Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA.

FEBS Open Bio
|September 19, 2024
PubMed

Insights

A novel YAP-TEAD disrupter, CA3, effectively reduces cholangiocarcinoma growth by targeting YAP-TEAD signaling. This therapy also activates compensatory androgen receptor signaling, suggesting dual inhibition as a promising treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cholangiocarcinoma (CCA) is an aggressive liver cancer with limited treatment options.
  • YAP-TEAD signaling is frequently activated in CCA, presenting a therapeutic target.
  • Developing novel therapies for CCA is crucial due to increasing incidence and mortality.

Purpose of the Study:

  • To evaluate the efficacy of CA3, a small-molecule YAP-TEAD disrupter, in preclinical models of CCA.
  • To investigate the molecular mechanisms underlying CA3's action in cancer cells.
  • To explore the potential of combining CA3 with androgen receptor blockade.

Main Methods:

  • Utilized CCA and gastric cancer cell lines and patient-derived xenograft (PDX) models.
  • Assessed CA3's effects on cell death, tumor growth, YAP-TEAD target gene expression, and protein levels.
  • Performed RNA sequencing to identify molecular pathways affected by CA3.
  • Investigated the impact of combined CA3 and androgen receptor blockade therapy.

Main Results:

  • CA3 induced cell death and delayed tumor growth in both FGFR2 fusion and wild-type CCA models.
  • CA3 decreased YAP-TEAD target gene expression, reporter activity, and TEAD levels without altering Hippo pathway signaling.
  • RNA sequencing revealed upregulation of androgen receptor-mediated transcription following CA3 exposure.
  • Combined therapy with CA3 and androgen receptor blockade enhanced cancer cell death.

Conclusions:

  • CA3 functions as a YAP-TEAD disrupter and demonstrates therapeutic efficacy in CCA models.
  • CA3 treatment leads to compensatory activation of androgen receptor signaling.
  • Dual inhibition of YAP-TEAD and androgen receptor pathways represents a potential therapeutic strategy for CCA.
Keywords:
Hippo pathwaybile duct tumorsenzalutamidefibroblast growth factor receptor

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