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

David A. Nathanson(University of California, Los Angeles), Beatrice Gini(Ludwig Cancer Research), Jack Mottahedeh(Neurobehavioral Systems), Koppany Visnyei(Neurobehavioral Systems), Tomoyuki Koga(Ludwig Cancer Research), German G. Gomez(Ludwig Cancer Research), Ascia Eskin(University of California, Los Angeles), Kiwook Hwang(California Institute of Technology), Jun Wang(California Institute of Technology), Kenta Masui(Ludwig Cancer Research), Andres A. Paucar(University of California, Los Angeles), Huijun Yang(Ludwig Cancer Research), Minori Ohashi(University of California, Los Angeles), Shaojun Zhu(Ludwig Cancer Research), Jill Wykosky(Ludwig Cancer Research), Rachel Reed(Ludwig Cancer Research), Stanley F. Nelson(University of California, Los Angeles), Timothy F. Cloughesy(University of California, Los Angeles), C. David James(University of California, San Francisco), P. Nagesh Rao(University of California, Los Angeles), Harley I. Kornblum(University of California, Los Angeles), James R. Heath(California Institute of Technology), Webster K. Cavenee(University of California San Diego), Frank B. Furnari(University of California San Diego), Paul S. Mischel(University of California San Diego)
Science
December 5, 2013
10.1126/science.1241328
Cited by 684Open Access
Full Text

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 adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.

Related Papers

No related papers found

Powered by citation graph analysis