Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

被引：450

作者：

Nathanson, David A. ^{[2
]}

Gini, Beatrice ^{[1
]}

Mottahedeh, Jack ^{[5
]}

Visnyei, Koppany ^{[5
]}

Koga, Tomoyuki ^{[1
]}

Gomez, German ^{[1
]}

Eskin, Ascia ^{[11
]}

Hwang, Kiwook ^{[3
,4
]}

Wang, Jun ^{[3
,4
]}

Masui, Kenta ^{[1
]}

Paucar, Andres ^{[2
,5
]}

Yang, Huijun ^{[1
]}

Ohashi, Minori ^{[2
]}

Zhu, Shaojun ^{[1
]}

Wykosky, Jill ^{[1
]}

Reed, Rachel ^{[1
]}

Nelson, Stanley F. ^{[11
]}

Cloughesy, Timothy F. ^{[7
,8
,9
]}

James, C. David ^{[6
]}

Rao, P. Nagesh ^{[10
]}

Kornblum, Harley I. ^{[2
,5
,7
,8
]}

Heath, James R. ^{[3
,4
]}

Cavenee, Webster K. ^{[1
,12
]}

Furnari, Frank B. ^{[1
,12
]}

Mischel, Paul S. ^{[1
,12
]}

机构：

[1] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[3] CALTECH, NanoSyst Biol Canc Ctr, Pasadena, CA 91030 USA

[4] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91030 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Neuropsychiat Inst, Los Angeles, CA 90095 USA

[6] Univ Calif San Francisco, San Francisco, CA 94143 USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Henry Singleton Brain Tumor Program, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[12] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA

来源：

SCIENCE | 2014年 / 343卷 / 6166期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR-RECEPTOR; DOUBLE-MINUTE CHROMOSOMES; HOMOGENEOUSLY STAINING REGIONS; DRUG-RESISTANCE; CELL-LINES; GLIOBLASTOMA-MULTIFORME; KINASE INHIBITORS; GENE; AMPLIFICATION; TUMORIGENICITY;

D O I：

10.1126/science.1241328

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：72 / 76

页数：5

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