Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells.

British Journal of Cancer
T TroianiFortunato Ciardiello

Abstract

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. 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. 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. This study provides molecular insights to explain resistance to an MEK inhibitor in h...Continue Reading

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Citations

Mar 29, 2014·Expert Opinion on Investigational Drugs·Morena FasanoFloriana Morgillo
Aug 12, 2014·Biochemical Society Transactions·Matthew J Sale, Simon J Cook
Jul 16, 2016·Oxidative Medicine and Cellular Longevity·Barbara MarengoCinzia Domenicotti
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Feb 20, 2016·Therapeutic Advances in Respiratory Disease·Omar Abdel-Rahman
Oct 15, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Teresa TroianiFortunato Ciardiello
May 9, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Teresa TroianiErika Martinelli
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Mar 11, 2018·Molecular Cancer Research : MCR·Yifeng XiaInder M Verma
Dec 10, 2020·Experimental Hematology & Oncology·Hongying ZhangHui Hua

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Methods Mentioned

BETA
xenograft
nuclear magnetic resonance
fluorescence-activated cell sorting
flow cytometry
xenografts
Feature Extraction
Assay
PCR
genotyping
antisense oligonucleotides

Software Mentioned

CurveExpert
Ensembl Design
Mass ARRAYTyper 4 Analyser
Agilent Feature Extraction
BMDP New System
CalcuSyn
Sequenom
Spectro READER
BMDP
Ingenuity

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