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Updated: Sep 5, 2025

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Suppression of heparan sulfation re-sensitizes YAP1-driven melanoma to MAPK pathway inhibitors

Sebastian M Dieter1,2,3,4, Domenica Lovecchio5, Abhijeet Pataskar5

  • 1Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. s.dieter@nki.nl.

Oncogene
|July 7, 2022
PubMed

Insights

Targeting YAP1/TAZ activity in melanoma, researchers found SLC35B2 is essential for drug resistance. Inhibiting SLC35B2 and heparan sulfation sensitizes resistant melanoma to BRAF inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Non-genetic mechanisms significantly contribute to cancer drug resistance.
  • Transcriptional co-activators YAP1 and TAZ are implicated in resistance to targeted therapies.
  • YAP1/TAZ-mediated resistance necessitates novel therapeutic strategies.

Purpose of the Study:

  • To identify genetic dependencies driving YAP1/TAZ activity in melanoma.
  • To explore therapeutic strategies for overcoming YAP1/TAZ-mediated drug resistance.
  • To investigate the role of SLC35B2 in melanoma drug resistance.

Main Methods:

  • Genome-wide CRISPR/Cas9 functional screening was employed.
  • YAP1/TAZ activity was assessed in MITFlow/AXLhigh melanoma models.
  • In vitro and in vivo experiments were conducted to evaluate therapeutic interventions.

Main Results:

  • High YAP1/TAZ activity was observed in MITFlow/AXLhigh melanomas resistant to MAPK pathway inhibition.
  • SLC35B2, a Golgi apparatus transporter, was identified as essential for YAP1/TAZ-driven drug resistance.
  • Loss of SLC35B2 decreased heparan sulfate expression and receptor tyrosine kinase activity, sensitizing resistant melanoma to BRAF inhibition.

Conclusions:

  • SLC35B2 is a critical determinant of drug resistance in YAP1/TAZ-active melanomas.
  • Targeting heparan sulfation via SLC35B2 offers a novel approach to overcome resistance to MAPK pathway inhibitors.
  • This study provides a new therapeutic avenue for treating resistant melanoma.

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