Publication Date:
2013-12-07
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049335/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049335/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nathanson, David A -- Gini, Beatrice -- Mottahedeh, Jack -- Visnyei, Koppany -- Koga, Tomoyuki -- Gomez, German -- Eskin, Ascia -- Hwang, Kiwook -- Wang, Jun -- Masui, Kenta -- Paucar, Andres -- Yang, Huijun -- Ohashi, Minori -- Zhu, Shaojun -- Wykosky, Jill -- Reed, Rachel -- Nelson, Stanley F -- Cloughesy, Timothy F -- James, C David -- Rao, P Nagesh -- Kornblum, Harley I -- Heath, James R -- Cavenee, Webster K -- Furnari, Frank B -- Mischel, Paul S -- NS73831/NS/NINDS NIH HHS/ -- P01 CA095616/CA/NCI NIH HHS/ -- P01-CA95616/CA/NCI NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- R01 NS052563/NS/NINDS NIH HHS/ -- R01 NS073831/NS/NINDS NIH HHS/ -- R01 NS080939/NS/NINDS NIH HHS/ -- R01-NS080939/NS/NINDS NIH HHS/ -- T32 CA009056/CA/NCI NIH HHS/ -- U54 CA151819/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 3;343(6166):72-6. doi: 10.1126/science.1241328. Epub 2013 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24310612" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antineoplastic Agents/*therapeutic use
;
Central Nervous System Neoplasms/*drug therapy/genetics
;
DNA/genetics
;
Drug Resistance, Neoplasm/*genetics
;
Erlotinib Hydrochloride
;
Glioblastoma/*drug therapy/genetics
;
Humans
;
Mice
;
*Molecular Targeted Therapy
;
Mutation
;
Neoplasm Transplantation
;
Protein Kinase Inhibitors/*therapeutic use
;
Quinazolines/therapeutic use
;
Receptor, Epidermal Growth Factor/antagonists & inhibitors/*genetics
;
Single-Cell Analysis
;
Tumor Cells, Cultured
;
Withholding Treatment
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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