There have been advances in personalized
therapy directed by molecular profiles in
lung adenocarcinoma, but not in lung
squamous cell carcinoma (SCC). The lack of actionable driver oncogenes in SCC has restricted the use of small-molecule inhibitors. Here, we show that SCC cell lines displayed differential sensitivities to
belinostat, a pan-
histone deacetylase inhibitor. Phosphoproteomic analysis of
belinostat-treated SCC cells revealed significant downregulation of the MAPK pathway, along with the induction of apoptosis. In
cisplatin-resistant cells that demonstrated aberrant MAPK activation, combined treatment with
belinostat significantly inhibited
cisplatin-induced ERK phosphorylation and exhibited strong synergistic cytotoxicity. Furthermore,
belinostat transcriptionally upregulated the
F-box proteins FBXO3 and FBXW10, which directly targeted son of sevenless (SOS), an upstream regulator of the MAPK pathway, for
proteasome-mediated degradation. Supporting this, suppression of SOS/ERK pathway by
belinostat could be abrogated by inhibiting proteasomal activity either with
bortezomib or with
siRNA knockdown of FBXO3/FBXW10. Taken together, these preclinical data offer a novel understanding of the epigenetic mechanism by which
belinostat exerts its cytotoxicity and supports the combination with
cisplatin in clinical settings for chemorefractory SCC
tumors.