MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with a MEK inhibitor

Arup Chakraborty, Robert W Robey, Victoria L Luchenko, Zhirong Zhan, Richard L Piekarz, Jean-Pierre Gillet, Andrew V Kossenkov, Julia Wilkerson, Louise C Showe, Michael M Gottesman, Nathan Collie, Susan E. Bates

Research output: Contribution to journalArticle

Abstract

To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat, and vorinostat. A custom TaqMan array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased protein expression and a four- to eightfold increase in mitogen-activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared with parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors, and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared with romidepsin treatment alone. Gene expression analysi
Original languageEnglish
Pages (from-to)4115-4125
JournalBlood/Amer. Soc. Hematology
StatePublished - Mar 26 2013

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    Chakraborty, A., Robey, R. W., Luchenko, V. L., Zhan, Z., Piekarz, R. L., Gillet, J-P., Kossenkov, A. V., Wilkerson, J., Showe, L. C., Gottesman, M. M., Collie, N., & Bates, S. E. (2013). MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with a MEK inhibitor. Blood/Amer. Soc. Hematology, 4115-4125.