title: Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA.
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.
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
authors: David A
authors: DA
authors: Nathanson
authors: Beatrice
authors: B
authors: Gini
authors: Jack
authors: J
authors: Mottahedeh
authors: Koppany
authors: K
authors: Visnyei
authors: Tomoyuki
authors: T
authors: Koga
authors: German
authors: G
authors: Gomez
authors: Ascia
authors: A
authors: Eskin
authors: Kiwook
authors: K
authors: Hwang
authors: Jun
authors: J
authors: Wang
authors: Kenta
authors: K
authors: Masui
authors: Andres
authors: A
authors: Paucar
authors: Huijun
authors: H
authors: Yang
authors: Minori
authors: M
authors: Ohashi
authors: Shaojun
authors: S
authors: Zhu
authors: Jill
authors: J
authors: Wykosky
authors: Rachel
authors: R
authors: Reed
authors: Stanley F
authors: SF
authors: Nelson
authors: Timothy F
authors: TF
authors: Cloughesy
authors: C David
authors: CD
authors: James
authors: P Nagesh
authors: PN
authors: Rao
authors: Harley I
authors: HI
authors: Kornblum
authors: James R
authors: JR
authors: Heath
authors: Webster K
authors: WK
authors: Cavenee
authors: Frank B
authors: FB
authors: Furnari
authors: Paul S
authors: PS
authors: Mischel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004247:DNA / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D059010:Single-Cell Analysis; D014407:Tumor Cells, Cultured; D028761:Withholding Treatment
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D004247:DNA; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors