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Published January 3, 2014 | Supplemental Material + Accepted Version
Journal Article Open

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


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.

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.

Attached Files

Accepted Version - nihms-572551.pdf

Supplemental Material - Nathanson.SM.Rev.pdf


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