title: Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647.
abstract: OBJECTIVE
  Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib. We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo.
  
  
  METHODS
  The activity of EGFR inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R and T790M mutant EGFR) xenograft tumors.
  
  
  RESULTS
  EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors.
  
  
  CONCLUSIONS
  These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.
authors.affiliation: Exelixis, Inc., South San Francisco, California 94083, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Gendreau
authors.forename: Richard
authors.initials: R
authors.lastname: Ventura
authors.forename: Paul
authors.initials: P
authors.lastname: Keast
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.forename: F Michael
authors.initials: FM
authors.lastname: Yakes
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Frauke
authors.initials: F
authors.lastname: Bentzien
authors.forename: Belinda
authors.initials: B
authors.lastname: Cancilla
authors.forename: Jeffery
authors.initials: J
authors.lastname: Lutman
authors.forename: Felix
authors.initials: F
authors.lastname: Chu
authors.forename: Lisa
authors.initials: L
authors.lastname: Jackman
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Shi
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Dana T
authors.initials: DT
authors.lastname: Aftab
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Jaeger
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Meyer
authors.forename: Anushka
authors.initials: A
authors.lastname: De Costa
authors.forename: Kelly
authors.initials: K
authors.lastname: Engell
authors.forename: Jason
authors.initials: J
authors.lastname: Chen
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.forename: Alison H
authors.initials: AH
authors.lastname: Joly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C571826:XL647; D000077156:Gefitinib