title: MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor.
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.
authors.affiliation: Department of Biological Sciences, Texas Tech University, Lubbock, TX, USA.
authors.forename: Arup R
authors.initials: AR
authors.lastname: Chakraborty
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Luchenko
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhan
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Collie
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D017322:Clinical Trials, Phase II as Topic; D047630:Depsipeptides / Q000008:administration & dosage*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011908:Rationalization; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C087123:romidepsin; D048369:MAP Kinase Kinase 1