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

• Published in: Blood 2013-05, Vol.121 (20), p.4115-4125
• Main Authors: Chakraborty, Arup R., Robey, Robert W., Luchenko, Victoria L., Zhan, Zhirong, Piekarz, Richard L., Gillet, Jean-Pierre, Kossenkov, Andrew V., Wilkerson, Julia, Showe, Louise C., Gottesman, Michael M., Collie, Nathan L., Bates, Susan E.
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Clinical Trials, Phase II as Topic; Depsipeptides - administration & dosage; Down-Regulation - drug effects; Down-Regulation - genetics; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - physiology; Enzyme Activation - drug effects; Enzyme Activation - physiology; Gene Expression Regulation, Neoplastic - drug effects; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - therapeutic use; Humans; Lymphoid Neoplasia; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - genetics; Lymphoma, T-Cell, Cutaneous - metabolism; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rationalization; Transcriptome; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-449140

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 analysis of samples obtained from patients with CTCL enrolled on the NCI1312 phase 2 study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials. •MAPK pathway activation and Bim loss may represent a fundamental mechanism of resistance to histone deacetylase inhibitors.•Combination of romidepsin with an MEK inhibitor may lead to greater responses in cancers in which the MAPK pathway is active.