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

Nathanson, David A. and Gini, Beatrice and Mottahedeh, Jack and Visnyei, Koppany and Koga, Tomoyuki and Gomez, German and Eskin, Ascia and Hwang, Kiwook and Wang, Jun and Masui, Kenta and Paucar, Andres and Yang, Huijun and Ohashi, Minori and Zhu, Shaojun and Wykosky, Jill and Reed, Rachel and Nelson, Stanley F. and Cloughesy, Timothy F. and James, C. David and Rao, P. Nagesh and Kornblum, Harley I. and Heath, James R. and Cavenee, Webster K. and Furnari, Frank B. and Mischel, Paul S. (2014) Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA. Science, 343 (6166). pp. 72-76. ISSN 0036-8075. PMCID PMC4049335.

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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.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Heath, James R.0000-0001-5356-4385
Additional Information:© 2014 American Association for the Advancement of Science. 3 June 2013; accepted 14 November 2013; published online 5 December 2013. This work was supported by the Ben and Catherine Ivy Foundation Fund (P.S.M., J.R.H., and T.F.C.); by National Institutes of Health (NIH) grants NS73831 (P.S.M.), U54 CA151819 (P.S.M. and J.R.H., principal investigator), P01-CA95616 (W.K.C. and F.B.F.), R01-NS080939 (F.B.F.), and NINDS R01 NS052563 (H.I.K.); and by the Ziering Family Foundation in memory of Sigi Ziering (T.F.C. and P.S.M.), the Art of the Brain Fund (T.F.C.), the James S. McDonnell Foundation (to F.B.F.), the European Commission PIOF-GA-2010-271819 (B.G.), Ruth L. Kirschstein Institutional National Research Service Award T32 CA009056 (D.A.N.), and the UCLA Scholars in Oncologic Molecular Imaging (SOMI) Program (D.A.N.). W.K.C. is a Fellow of the National Foundation for Cancer Research. We thank R. Kolodner for careful reading of the manuscript and helpful suggestions. We also thank W. Yong and the UCLA Brain Tumor Translational Resource.
Funding AgencyGrant Number
Ben and Catherine Ivy Foundation FundUNSPECIFIED
NIHU54 CA151819
Ziering Family FoundationUNSPECIFIED
Art of the Brain FundUNSPECIFIED
James S. McDonnell FoundationUNSPECIFIED
European CommissionPIOF-GA-2010-271819
NIH Predoctoral FellowshipT32 CA009056
UCLA Scholars in Oncologic Molecular Imaging (SOMI) ProgramUNSPECIFIED
National Foundation for Cancer ResearchUNSPECIFIED
Issue or Number:6166
PubMed Central ID:PMC4049335
Record Number:CaltechAUTHORS:20140124-111345325
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:43512
Deposited By: Jason Perez
Deposited On:24 Jan 2014 21:05
Last Modified:03 Oct 2019 06:08

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