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

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/AXL(high) 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.

Automated summary

Accumulating evidence suggests that non-genetic mechanisms play a substantial role in drug resistance in cancer patients. This study identifies the transcriptional co-activators YAP1 and TAZ as important contributors to resistance to targeted therapies. By using a genome-wide CRISPR/Cas9 functional screen, the study identifies SLC35B2 as an essential gene for YAP1/TAZ-driven drug resistance. Inhibition of SLC35B2 sensitizes resistant melanoma cells to BRAF inhibition, providing a potential therapeutic strategy to overcome resistance.