Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.8692
Title: Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer
Authors: Bhattacharya B. 
Low S.H.H. 
Chong M.L. 
Chia D.
Koh K.X.
Sapari N.S. 
Kaye S.
Hung H.
Benoukraf T. 
Soong R. 
Keywords: buparlisib
endothelin
endothelin 1
selumetinib
transforming growth factor beta2
antineoplastic agent
mitogen activated protein kinase kinase kinase
phosphatidylinositol 3 kinase
protein kinase inhibitor
acquired resistance
animal experiment
animal model
animal tissue
antineoplastic activity
Article
cancer combination chemotherapy
cancer resistance
cell stimulation
colorectal cancer
controlled study
cross resistance
drug efficacy
drug potentiation
EDN1 gene
gene overexpression
gene silencing
genome analysis
HCT116 cell line
human
human cell
IC50
in vitro study
in vivo study
male
mouse
nonhuman
phenotype
signal transduction
TGFB2 gene
animal
antagonists and inhibitors
colorectal tumor
drug potentiation
drug resistance
drug screening
HCT 116 cell line
pathology
physiology
SCID mouse
Animals
Antineoplastic Combined Chemotherapy Protocols
Colorectal Neoplasms
Drug Resistance, Neoplasm
Drug Synergism
HCT116 Cells
Humans
MAP Kinase Kinase Kinases
Mice
Mice, SCID
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
Issue Date: 2016
Citation: Bhattacharya B., Low S.H.H., Chong M.L., Chia D., Koh K.X., Sapari N.S., Kaye S., Hung H., Benoukraf T., Soong R. (2016). Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer. Oncotarget 7 (20) : 29187-29198. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.8692
Abstract: Historically, understanding of acquired resistance (AQR) to combination treatment has been based on knowledge of resistance to its component agents. To test whether an altered drug interaction could be an additional factor in AQR to combination treatment, models of AQR to combination and single agent MEK and PI3K inhibitor treatment were generated. Combination indices indicated combination treatment of PI3K and MEK inhibitors remained synergistic in cells with AQR to single agent but not combination AQR cells. Differences were also observed between the models in cellular phenotypes, pathway signaling and drug cross-resistance. Genomics implicated TGFB2-EDN1 overexpression as candidate determinants in models of AQR to combination treatment. Supplementation of endothelin in parental cells converted synergism to antagonism. Silencing of TGFB2 or EDN1 in cells with AQR conferred synergy between PI3K and MEK inhibitor. These results highlight that AQR to combination treatment may develop through alternative mechanisms to those of single agent treatment, including a change in drug interaction.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/174090
ISSN: 19492553
DOI: 10.18632/oncotarget.8692
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