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

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Science  05 Dec 2013:
1241328
DOI: 10.1126/science.1241328

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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 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, re-emergence 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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