title: Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.
abstract: BACKGROUND
  MEK is activated in ∼40% colorectal cancer (CRC) and 20-30% non-small cell lung cancer (NSCLC). Selumetinib is a selective inhibitor of MEK1/2, which is currently in clinical development.
  
  
  METHODS
  We evaluated the effects of selumetinib in vitro and in vivo in CRC and NSCLC cell lines to identify cancer cell characteristics correlating with sensitivity to MEK inhibition.
  
  
  RESULTS
  Five NSCLC and six CRC cell lines were treated with selumetinib and classified according to the median inhibitory concentration (IC(50)) values as sensitive (≤1 μM) or resistant (>1 μM). In selumetinib-sensitive cancer cell lines, selumetinib treatment induced G1 cell-cycle arrest and apoptosis and suppression of tumour growth as xenografts in immunodeficient mice. Evaluation of intracellular effector proteins and analysis of gene mutations showed no correlation with selumetinib sensitivity. Microarray gene expression profiles revealed that the activation of cAMP-dependent protein kinase A (PKA) was associated with MEK inhibitor resistance. Combined targeting of both MEK and PKA resulted in cancer cell growth inhibition of MEK inhibitor-resistant cancer cell lines in vitro and in vivo.
  
  
  CONCLUSIONS
  This study provides molecular insights to explain resistance to an MEK inhibitor in human cancer cell lines.
authors.affiliation: Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Seconda Università degli Studi di Napoli, Via S. Pansini 5, Napoli 80131, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Troiani
authors.forename: L
authors.initials: L
authors.lastname: Vecchione
authors.forename: E
authors.initials: E
authors.lastname: Martinelli
authors.forename: A
authors.initials: A
authors.lastname: Capasso
authors.forename: S
authors.initials: S
authors.lastname: Costantino
authors.forename: L P
authors.initials: LP
authors.lastname: Ciuffreda
authors.forename: F
authors.initials: F
authors.lastname: Morgillo
authors.forename: D
authors.initials: D
authors.lastname: Vitagliano
authors.forename: E
authors.initials: E
authors.lastname: D'Aiuto
authors.forename: R
authors.initials: R
authors.lastname: De Palma
authors.forename: S
authors.initials: S
authors.lastname: Tejpar
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: M
authors.initials: M
authors.lastname: De Lorenzi
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.forename: L
authors.initials: L
authors.lastname: Berrino
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D017868:Cyclic AMP-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases