Journal
SCIENCE
Volume 343, Issue 6166, Pages 72-76Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1241328
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Funding
- Ben and Catherine Ivy Foundation
- National Institutes of Health (NIH) [NS73831, U54 CA151819, P01-CA95616, R01-NS080939, NINDS R01 NS052563]
- Ziering Family Foundation
- Art of the Brain Fund
- James S. McDonnell Foundation
- European Commission [PIOF-GA-2010-271819]
- Ruth L. Kirschstein Institutional National Research Service Award [T32 CA009056]
- UCLA Scholars in Oncologic Molecular Imaging (SOMI) Program
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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.
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