PMID- 19238210
OWN - NLM
STAT- MEDLINE
DCOM- 20090413
LR  - 20220318
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 4
IP  - 2
DP  - 2009
TI  - Alterations in genes of the EGFR signaling pathway and their relationship to EGFR 
      tyrosine kinase inhibitor sensitivity in lung cancer cell lines.
PG  - e4576
LID - 10.1371/journal.pone.0004576 [doi]
LID - e4576
AB  - BACKGROUND: Deregulation of EGFR signaling is common in non-small cell lung 
      cancers (NSCLC) and this finding led to the development of tyrosine kinase 
      inhibitors (TKIs) that are highly effective in a subset of NSCLC. Mutations of 
      EGFR (mEGFR) and copy number gains (CNGs) of EGFR (gEGFR) and HER2 (gHER2) have 
      been reported to predict for TKI response. Mutations in KRAS (mKRAS) are 
      associated with primary resistance to TKIs. METHODOLOGY/PRINCIPAL FINDINGS: We 
      investigated the relationship between mutations, CNGs and response to TKIs in a 
      large panel of NSCLC cell lines. Genes studied were EGFR, HER2, HER3 HER4, KRAS, 
      BRAF and PIK3CA. Mutations were detected by sequencing, while CNGs were 
      determined by quantitative PCR (qPCR), fluorescence in situ hybridization (FISH) 
      and array comparative genomic hybridization (aCGH). IC50 values for the TKIs 
      gefitinib (Iressa) and erlotinib (Tarceva) were determined by MTS assay. For any 
      of the seven genes tested, mutations (39/77, 50.6%), copy number gains (50/77, 
      64.9%) or either (65/77, 84.4%) were frequent in NSCLC lines. Mutations of EGFR 
      (13%) and KRAS (24.7%) were frequent, while they were less frequent for the other 
      genes. The three techniques for determining CNG were well correlated, and qPCR 
      data were used for further analyses. CNGs were relatively frequent for EGFR and 
      KRAS in adenocarcinomas. While mutations were largely mutually exclusive, CNGs 
      were not. EGFR and KRAS mutant lines frequently demonstrated mutant allele 
      specific imbalance i.e. the mutant form was usually in great excess compared to 
      the wild type form. On a molar basis, sensitivity to gefitinib and erlotinib were 
      highly correlated. Multivariate analyses led to the following results: 1. mEGFR 
      and gEGFR and gHER2 were independent factors related to gefitinib sensitivity, in 
      descending order of importance. 2. mKRAS was associated with increased in vitro 
      resistance to gefitinib. CONCLUSIONS/SIGNIFICANCE: Our in vitro studies confirm 
      and extend clinical observations and demonstrate the relative importance of both 
      EGFR mutations and CNGs and HER2 CNGs in the sensitivity to TKIs.
FAU - Gandhi, Jeet
AU  - Gandhi J
AD  - Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern 
      Medical Center at Dallas, Dallas, Texas, United States of America.
FAU - Zhang, Jianling
AU  - Zhang J
FAU - Xie, Yang
AU  - Xie Y
FAU - Soh, Junichi
AU  - Soh J
FAU - Shigematsu, Hisayuki
AU  - Shigematsu H
FAU - Zhang, Wei
AU  - Zhang W
FAU - Yamamoto, Hiromasa
AU  - Yamamoto H
FAU - Peyton, Michael
AU  - Peyton M
FAU - Girard, Luc
AU  - Girard L
FAU - Lockwood, William W
AU  - Lockwood WW
FAU - Lam, Wan L
AU  - Lam WL
FAU - Varella-Garcia, Marileila
AU  - Varella-Garcia M
FAU - Minna, John D
AU  - Minna JD
FAU - Gazdar, Adi F
AU  - Gazdar AF
LA  - eng
GR  - P50 CA070907/CA/NCI NIH HHS/United States
GR  - U01 CA084971/CA/NCI NIH HHS/United States
GR  - U01CA084971/CA/NCI NIH HHS/United States
GR  - P50CA70907/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090224
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (KRAS protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Quinazolines)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Carcinoma, Non-Small-Cell Lung/*genetics/pathology
MH  - Cell Line, Tumor
MH  - DNA Mutational Analysis
MH  - ErbB Receptors/*genetics/metabolism
MH  - Gefitinib
MH  - Gene Dosage
MH  - Humans
MH  - *Mutation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - Quinazolines/pharmacology
MH  - Receptor, ErbB-2/*genetics
MH  - Signal Transduction/*genetics
MH  - ras Proteins/*genetics
PMC - PMC2642732
COIS- Competing Interests: Dr. Gazdar is a paid consultant/lecturer for AstraZeneca 
      PLC. Dr. Garcia recieves Research Funding >10,000 from AstraZeneca, Genentech and 
      OSI; Honorarium <10,000 from Roche. Dr. Minna receives research support from 
      AstraZeneca PLC.
EDAT- 2009/02/25 09:00
MHDA- 2009/04/14 09:00
PMCR- 2009/02/24
CRDT- 2009/02/25 09:00
PHST- 2008/09/16 00:00 [received]
PHST- 2008/12/18 00:00 [accepted]
PHST- 2009/02/25 09:00 [entrez]
PHST- 2009/02/25 09:00 [pubmed]
PHST- 2009/04/14 09:00 [medline]
PHST- 2009/02/24 00:00 [pmc-release]
AID - 08-PONE-RA-06424R1 [pii]
AID - 10.1371/journal.pone.0004576 [doi]
PST - ppublish
SO  - PLoS One. 2009;4(2):e4576. doi: 10.1371/journal.pone.0004576. Epub 2009 Feb 24.