Melanoma: HDAC8 regulates resistance to BRAF inhibitors

  • Emmons MF & al.
  • Cancer Res
  • 15 Apr 2019

  • curated by Deepa Koli
  • Univadis Clinical Summaries
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Takeaway

  • Melanomas when exposed to multiple stresses, including BRAF inhibitor therapy, hypoxia, and UV irradiation leads to an increase in histone deacetylase 8 (HDAC8) expression.
  • Mechanisms of resistance are mediated through receptor tyrosine kinase activation.
  • HDAC8-specific inhibitors may limit resistance to BRAF inhibitor therapy.

Why this matters

  • Many patients with melanoma eventually develop drug resistance.
  • Findings call for development of more selective and potent HDAC8 inhibitors that can limit phenotype switching of melanoma cells.

Key highlights

  • HDAC8 expression was consistently higher in BRAF-resistant melanoma cell lines.
  • HDAC8 inhibitor restored the sensitivity of BRAF inhibitor resistant melanoma cell lines to vemurafenib.
  • HDAC8 overexpression regulated epithelial mesenchymal transition (EMT), MAPK, and AP-1 signaling in drug-naïve BRAF-mutant melanoma cell lines.
  • HDAC8 introduction altered the basal phosphorylation of multiple receptor tyrosine kinases (RTKs), including EGFR, c-MET, and FGFR3 and also increased c-Jun phosphorylation after BRAF inhibitor treatment.
  • RTK activation mediates HDAC8-mediated BRAF inhibitor resistance leading to MAPK signaling.
  • HDAC8 increases MAPK activity in melanoma cells through deacetylation of c‐Jun.
  • In isogenic mice melanoma cells, BRAF and HDAC inhibitors reduced tumor growth vs either agent alone and was associated with durable responses.