- 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.
- 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.