A study of mechanisms of resistance to the histone deacetylase inhibitor romidepsin in a cutaneous T-cell lymphoma model

Date

2011-12

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Abstract

Acquired resistance to histone deacetylase inhibitors (HDIs), a new group of anti-cancer agents, limits their clinical efficacy. A detailed understanding of the mechanisms of resistance to HDIs may lead to strategies designed to increase clinical efficacy. In the present study, the HuT 78 cutaneous T-cell lymphoma cell line was exposed to increasing concentrations of romidepsin in the presence of the P-glycoprotein (Pgp) inhibitors verapamil or valspodar (PSC833) to prevent the emergence of Pgp, a known resistance mechanism. This resulted in the establishment of three independently- selected sublines: HuT 78 DpVp 35, DpVp 50, and DpP 75. The romidepsin-resistant sublines are approximately 100-200- fold resistant to romidepsin and are not cross- resistant to the HDIs belinostat, panobinostat or vorinostat. Low but detectable levels of Pgp did not explain the resistance as treating the cells with romidepsin in the presence of the Pgp inhibitor tariquidar did not significantly reverse resistance. A custom-made Taqman low density gene expression array detected increased expression of insulin receptor (IR) in the resistant cells that was confirmed by immunoblot analysis. Increased activation of mitogen activated protein kinase kinase (MEK), a downstream effector of the IR pathway, was also observed in the resistant cells compared to the parental cells. Interestingly, resistant cells were found to be exquisitely sensitive to MEK inhibition but not to phosphatidylinositol 3-kinase (PI3K) inhibition or extracellular signal-regulated kinase (ERK) inhibition. Combined treatment of romidepsin with low concentrations of MEK inhibitor also resulted in increased cell death in HuT 78 DpVp 50 cells. The exquisite sensitivity to MEK inhibition in the resistant sublines was found to correlate with restoration of the expression of Bim, a Bcl-2-homology domain-3 only (BH-3) proapoptotic protein. These findings implicate increased phosphorylation of MEK as a mechanism of resistance to romidepsin and suggest combination of romidepsin with MEK inhibitors in future clinical trials.

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Keywords

Biology, Romidepsin, Cutaneous T-cell, MAPK pathway, Bim, Histone deacetylase inhibitors

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