title: Kinetics of inhibitor cycling underlie therapeutic disparities between EGFR-driven lung and brain cancers.
abstract: Although mutational activation of the epidermal growth factor receptor (EGFR) features prominently in glioma and non-small cell lung cancer (NSCLC), inhibitors of EGFR improve survival only in patients with NCSLC. To understand how mutations in EGFR influence response to therapy, we generated glioma cells expressing either glioma- or NSCLC-derived alleles and quantified kinase-site occupancy by clinical inhibitors with the use of a novel affinity probe and kinetic methodology. At equivalent doses, erlotinib achieved lower kinase-site occupancy in glioma-derived EGFRvIII compared with NSCLC-derived EGFR mutants. Kinase-site occupancy correlated directly with cell-cycle arrest. EGFRvIII released erlotinib rapidly compared with wild-type EGFR, whereas NSCLC-derived mutants released erlotinib slowly.
  
  
  CONCLUSIONS
  These data suggest that kinase-site occupancy is a biomarker for efficacy of EGFR inhibitors, that rapid binding and release of erlotinib in glioma-derived EGFRvIII opposes the blockade of downstream signaling, and that slower cycling of erlotinib within the active site of NSCLC-derived mutants underlies their improved clinical response.
authors.affiliation: Department of Neurology, Brain Tumor Research Center, San Francisco, CA 94143, USA.
authors.forename: Krister J
authors.initials: KJ
authors.lastname: Barkovich
authors.forename: Sujatmi
authors.initials: S
authors.lastname: Hariono
authors.forename: Adam L
authors.initials: AL
authors.lastname: Garske
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jimmy A
authors.initials: JA
authors.lastname: Blair
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Fan
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors