MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor.
Blood, 2013/5/16;121(20):4115-25.
Chakraborty AR[1], Robey RW, Luchenko VL, Zhan Z, Piekarz RL, Gillet JP, Kossenkov AV, Wilkerson J, Showe LC, Gottesman MM, Collie NL, Bates SE
Affiliations
PMID: 23532732DOI: 10.1182/blood-2012-08-449140
Impact factor: 25.476
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 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.
MeSH terms
Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Clinical Trials, Phase II as Topic; Depsipeptides; Down-Regulation; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Enzyme Activation; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Cutaneous; MAP Kinase Kinase 1; MAP Kinase Signaling System; Membrane Proteins; Oligonucleotide Array Sequence Analysis; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Rationalization; Transcriptome; Tumor Cells, Cultured
More resources
Full text:
Europe PubMed Central; PubMed Central
EndNote: Download