PMID- 24310612
OWN - NLM
STAT- MEDLINE
DCOM- 20140123
LR  - 20211021
IS  - 1095-9203 (Electronic)
IS  - 0036-8075 (Print)
IS  - 0036-8075 (Linking)
VI  - 343
IP  - 6166
DP  - 2014 Jan 3
TI  - Targeted therapy resistance mediated by dynamic regulation of extrachromosomal 
      mutant EGFR DNA.
PG  - 72-6
LID - 10.1126/science.1241328 [doi]
AB  - Intratumoral heterogeneity contributes to cancer drug resistance, but the 
      underlying mechanisms are not understood. Single-cell analyses of patient-derived 
      models and clinical samples from glioblastoma patients treated with epidermal 
      growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that 
      tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring 
      distinct cellular phenotypes to reach an optimal equilibrium for growth. 
      Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from 
      extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations 
      on extrachromosomal DNA follows. These results indicate a highly specific, 
      dynamic, and adaptive route by which cancers can evade therapies that target 
      oncogenes maintained on extrachromosomal DNA.
FAU - Nathanson, David A
AU  - Nathanson DA
AD  - Ludwig Institute for Cancer Research, University of California at San Diego, La 
      Jolla, CA, USA.
FAU - Gini, Beatrice
AU  - Gini B
FAU - Mottahedeh, Jack
AU  - Mottahedeh J
FAU - Visnyei, Koppany
AU  - Visnyei K
FAU - Koga, Tomoyuki
AU  - Koga T
FAU - Gomez, German
AU  - Gomez G
FAU - Eskin, Ascia
AU  - Eskin A
FAU - Hwang, Kiwook
AU  - Hwang K
FAU - Wang, Jun
AU  - Wang J
FAU - Masui, Kenta
AU  - Masui K
FAU - Paucar, Andres
AU  - Paucar A
FAU - Yang, Huijun
AU  - Yang H
FAU - Ohashi, Minori
AU  - Ohashi M
FAU - Zhu, Shaojun
AU  - Zhu S
FAU - Wykosky, Jill
AU  - Wykosky J
FAU - Reed, Rachel
AU  - Reed R
FAU - Nelson, Stanley F
AU  - Nelson SF
FAU - Cloughesy, Timothy F
AU  - Cloughesy TF
FAU - James, C David
AU  - James CD
FAU - Rao, P Nagesh
AU  - Rao PN
FAU - Kornblum, Harley I
AU  - Kornblum HI
FAU - Heath, James R
AU  - Heath JR
FAU - Cavenee, Webster K
AU  - Cavenee WK
FAU - Furnari, Frank B
AU  - Furnari FB
FAU - Mischel, Paul S
AU  - Mischel PS
LA  - eng
GR  - T32 GM008042/GM/NIGMS NIH HHS/United States
GR  - R01-NS080939/NS/NINDS NIH HHS/United States
GR  - P01 CA095616/CA/NCI NIH HHS/United States
GR  - U54 CA151819/CA/NCI NIH HHS/United States
GR  - NS73831/NS/NINDS NIH HHS/United States
GR  - R01 NS080939/NS/NINDS NIH HHS/United States
GR  - P01-CA95616/CA/NCI NIH HHS/United States
GR  - U54 CA119347/CA/NCI NIH HHS/United States
GR  - R01 NS052563/NS/NINDS NIH HHS/United States
GR  - R01 NS073831/NS/NINDS NIH HHS/United States
GR  - T32 CA009056/CA/NCI NIH HHS/United States
GR  - P30 CA023100/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131205
PL  - United States
TA  - Science
JT  - Science (New York, N.Y.)
JID - 0404511
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 9007-49-2 (DNA)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Central Nervous System Neoplasms/*drug therapy/genetics
MH  - DNA/genetics
MH  - Drug Resistance, Neoplasm/*genetics
MH  - ErbB Receptors/antagonists & inhibitors/*genetics
MH  - Erlotinib Hydrochloride
MH  - Glioblastoma/*drug therapy/genetics
MH  - Humans
MH  - Mice
MH  - *Molecular Targeted Therapy
MH  - Mutation
MH  - Neoplasm Transplantation
MH  - Protein Kinase Inhibitors/*therapeutic use
MH  - Quinazolines/therapeutic use
MH  - Single-Cell Analysis
MH  - Tumor Cells, Cultured
MH  - Withholding Treatment
PMC - PMC4049335
MID - NIHMS572551
EDAT- 2013/12/07 06:00
MHDA- 2014/01/24 06:00
PMCR- 2015/01/03
CRDT- 2013/12/07 06:00
PHST- 2013/12/07 06:00 [entrez]
PHST- 2013/12/07 06:00 [pubmed]
PHST- 2014/01/24 06:00 [medline]
PHST- 2015/01/03 00:00 [pmc-release]
AID - science.1241328 [pii]
AID - 10.1126/science.1241328 [doi]
PST - ppublish
SO  - Science. 2014 Jan 3;343(6166):72-6. doi: 10.1126/science.1241328. Epub 2013 Dec 
      5.