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

Nathanson, David A.; Gini, Beatrice; Mottahedeh, Jack; Visnyei, Koppany; Koga, Tomoyuki; Gomez, German G.; Eskin, Ascia; Hwang, Kiwook; Wang, Jun; Masui, Kenta; Paucar, Andres A.; 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.

doi:10.1126/science.1241328

articleScienceDec 5, 2013GREEN OA

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

DADavid A. Nathanson BGBeatrice Gini JMJack Mottahedeh KVKoppany Visnyei TKTomoyuki Koga

University of California, Los Angeles · Ludwig Cancer Research · +4 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

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…

Citation impact

684

total citations

FWCI: 11.20
Percentile: 100%
References: 34

Citations per year

Authors

25

Topics & keywords

Topics

Keywords

Extrachromosomal DNA
Erlotinib
Epidermal growth factor receptor
Drug resistance
Mutant
Cancer research
Mutation
Cancer

UN Sustainable Development Goals

Good health and well-being

No related works found for this paper.