Acquired resistance to vorinostat in cutaneous T cell lymphoma involves augmented ERK phosphorylation

Background: Vorinostat is the first approved histone deacetylase inhibitor used in many countries for treating advanced cutaneous T-cell lymphoma (CTCL). However, prolong application of this drug leads to the development of resistance. This study aims to understand mechanistic basis for acquired resistance to vorinostat in CTCL cells. Methods: We established a vorinostat resistant clone of human CTCL line HuT78 (HuT78vr) by selecting cells in increasing drug concentrations for over 6 months. Molecular characterization of cells was performed by SILAC, RNA sequencing, flow-cytometry, and expression analysis. Findings: Vorinostat resistant HuT78vr cells exhibited increased cellular invasiveness and enhanced drug-efflux ability. Transcriptomic and proteomic analysis revealed defective cell adhesion and apoptosis in HuT78vr cells, which expressed significantly high levels of the adhesion protein LAIR2. The mitogen-activated protein kinase signaling was significantly upregulated while pro-caspase 3 was downregulated in HuT78vr cells. Intriguingly, HuT78vr cells gained cross-resistance to commonly used inhibitors of histone deacetylase and topoisomerase, but remained sensitive to inhibitors of STAT3, LAIR2 and ERK. Interpretation: Our comprehensive analysis highlights elevated LAIR2 expression and constitutive ERK phosphorylation as key predictors in acquired resistance to vorinostat in CTCL. Funding: This study was supported, in part, by Start-Up Grant to NKV provided by Lee Kong Chian School of Medicine, Nanyang Technological University Singapore (L0412290), the National Research Foundation Singapore under its Open Fund Large Collaborative Grant (OFLCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), the Singapore Therapeutics Development Review (H22G9a0014), A*STAR, Singapore, and the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 1 Grant (RG26/20),. AK, and ZSP were provided with PhD fellowship by Lee Kong Chian School of Medicine, Nanyang Technological University Singapore. SB received a fellowship from the German Academic Exchange Service. Declaration of Interest: The authors declare no competing financial interests.