2. Academic Validation
  3. Suppression of heparan sulfation re-sensitizes YAP1-driven melanoma to MAPK pathway inhibitors

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

  • Oncogene. 2022 Aug;41(32):3953-3968. doi: 10.1038/s41388-022-02400-z.
Sebastian M Dieter 1 2 3 4,  Domenica Lovecchio 5,  Abhijeet Pataskar 5,  Martina K Zowada 6,  Pierre-René Körner 5,  Anna Khalizieva 5,  Olaf van Tellingen 7,  Dirk Jäger 8 9,  Hanno Glimm 10 8 9 11 12,  Reuven Agami 13 14
Affiliations

Affiliations

  • 1 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. s.dieter@nki.nl.
  • 2 Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. s.dieter@nki.nl.
  • 3 Department of Medical Oncology, Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany. s.dieter@nki.nl.
  • 4 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany. s.dieter@nki.nl.
  • 5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 6 Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7 Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 8 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany.
  • 9 German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 10 Department of Medical Oncology, Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.
  • 11 Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany.
  • 12 German Cancer Consortium (DKTK), Dresden, Germany.
  • 13 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. r.agami@nki.nl.
  • 14 Erasmus MC, Rotterdam University, Rotterdam, The Netherlands. r.agami@nki.nl.
PMID: 35798875 DOI: 10.1038/s41388-022-02400-z
Abstract

Accumulating evidence identifies non-genetic mechanisms substantially contributing to drug resistance in Cancer patients. Preclinical and clinical data implicate the transcriptional co-activators YAP1 and its paralog TAZ in resistance to multiple targeted therapies, highlighting the strong need for therapeutic strategies overcoming YAP1/TAZ-mediated resistance across tumor entities. Here, we show particularly high YAP1/TAZ activity in MITFlow/AXLhigh melanomas characterized by resistance to MAPK pathway inhibition and broad receptor tyrosine kinase activity. To uncover genetic dependencies of melanoma cells with high YAP1/TAZ activity, we used a genome-wide CRISPR/Cas9 functional screen and identified SLC35B2, the 3'-phosphoadenosine-5'-phosphosulfate transporter of the Golgi apparatus, as an essential gene for YAP1/TAZ-driven drug resistance. SLC35B2 expression correlates with tumor progression, and its loss decreases heparan sulfate expression, reduces receptor tyrosine kinase activity, and sensitizes resistant melanoma cells to BRaf inhibition in vitro and in vivo. Thus, targeting heparan sulfation via SLC35B2 represents a novel approach for breaking receptor tyrosine kinase-mediated resistance to MAPK pathway inhibitors.

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