PMID- 24009623
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20130906
LR  - 20220318
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 4
DP  - 2013
TI  - Genome-wide association study for biomarker identification of Rapamycin and 
      Everolimus using a lymphoblastoid cell line system.
PG  - 166
LID - 10.3389/fgene.2013.00166 [doi]
LID - 166
AB  - The mammalian target of rapamycin (mTOR) inhibitors, a set of promising potential 
      anti-cancer agents, has shown response variability among individuals. This study 
      aimed to identify novel biomarkers and mechanisms that might influence the 
      response to Rapamycin and Everolimus. Genome-wide association (GWA) analyses 
      involving single nucleotide polymorphisms (SNPs), mRNA, and microRNAs microarray 
      data were assessed for association with area under the cytotoxicity dose response 
      curve (AUC) of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs). 
      Integrated analysis among SNPs, expression data, microRNA data and AUC values 
      were also performed to help select candidate genes for further functional 
      characterization. Functional validation of candidate genes using siRNA screening 
      in multiple cell lines followed by MTS assays for the two mTOR inhibitors were 
      performed. We found that 16 expression probe sets (genes) that overlapped between 
      the two drugs were associated with AUC values of two mTOR inhibitors. One hundred 
      and twenty seven and one hundred SNPs had P < 10(-4), while 8 and 10 SNPs had P < 
      10(-5) with Rapamycin and Everolimus AUC, respectively. Functional studies 
      indicated that 13 genes significantly altered cell sensitivity to either one or 
      both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was 
      significantly associated with AUC values for both drugs and was shown to repress 
      expression of genes that were associated with AUC and desensitize cells to both 
      drugs. In summary, this study identified genes and a microRNA that might 
      contribute to response to mTOR inhibitors.
FAU - Jiang, Jing
AU  - Jiang J
AD  - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic 
      Rochester, MN, USA.
FAU - Fridley, Brooke L
AU  - Fridley BL
FAU - Feng, Qiping
AU  - Feng Q
FAU - Abo, Ryan P
AU  - Abo RP
FAU - Brisbin, Abra
AU  - Brisbin A
FAU - Batzler, Anthony
AU  - Batzler A
FAU - Jenkins, Gregory
AU  - Jenkins G
FAU - Long, Pamela A
AU  - Long PA
FAU - Wang, Liewei
AU  - Wang L
LA  - eng
GR  - R01 CA138461/CA/NCI NIH HHS/United States
GR  - U19 GM061388/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20130830
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC3757297
OTO - NOTNLM
OT  - Everolimus
OT  - Rapamycin
OT  - genome-wide association
OT  - mTOR
OT  - pharmacogenomics
EDAT- 2013/09/07 06:00
MHDA- 2013/09/07 06:01
PMCR- 2013/08/30
CRDT- 2013/09/07 06:00
PHST- 2013/07/02 00:00 [received]
PHST- 2013/08/10 00:00 [accepted]
PHST- 2013/09/07 06:00 [entrez]
PHST- 2013/09/07 06:00 [pubmed]
PHST- 2013/09/07 06:01 [medline]
PHST- 2013/08/30 00:00 [pmc-release]
AID - 10.3389/fgene.2013.00166 [doi]
PST - epublish
SO  - Front Genet. 2013 Aug 30;4:166. doi: 10.3389/fgene.2013.00166. eCollection 2013.