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The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype

Sivaveera Kandasamy1, Gautam Adhikary2, Ellen A Rorke3

  • 1Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.

Molecular Cancer Research : MCR
|November 17, 2019
PubMed

Insights

Targeting YAP1/TAZ/TEAD signaling with verteporfin or CA3 inhibits mesothelioma cancer stem cells. This approach reduces tumor formation and increases apoptosis, offering a potential new treatment strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Mesothelioma is an aggressive cancer with poor prognosis, often arising from asbestos exposure.
  • Current treatments like surgery and chemotherapy are initially effective but lead to therapy-resistant recurrent tumors.
  • Mesothelioma cancer stem cells (MCS) drive tumor maintenance and drug resistance.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting YAP1/TAZ/TEAD signaling in MCS cells.
  • To evaluate the efficacy of YAP1 signaling inhibitors verteporfin and CA3 in preclinical mesothelioma models.

Main Methods:

  • Treatment of MCS cells with YAP1 signaling inhibitors verteporfin and CA3.
  • Assessment of inhibitor effects on MCS cell phenotype, including spheroid formation, invasion, migration, and apoptosis.
  • Evaluation of YAP1/TEAD signaling levels and activity.
  • Testing efficacy in both epithelioid and sarcomatoid mesothelioma cell lines.

Main Results:

  • Verteporfin and CA3 treatment attenuated the MCS cell phenotype, suppressing spheroid formation, invasion, and migration.
  • Inhibitors reduced YAP1/TEAD levels/activity and increased MCS cell apoptosis.
  • Constitutively active YAP1 expression counteracted inhibitor effects, confirming YAP1/TAZ/TEAD pathway dependency.
  • Agents showed activity against both peritoneal and pleural mesothelioma cells.

Conclusions:

  • Inhibition of YAP1/TAZ/TEAD signaling is a promising strategy for overcoming mesothelioma drug resistance.
  • Verteporfin and CA3 demonstrate potential as novel therapeutic agents for mesothelioma treatment.
  • Targeting this pathway may offer a viable approach for managing aggressive mesothelioma, including resistant subtypes.

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