title: Noncovalent wild-type-sparing inhibitors of EGFR T790M.
abstract: Approximately half of EGFR-mutant non-small cell lung cancer (NSCLC) patients treated with small-molecule EGFR kinase inhibitors develop drug resistance associated with the EGF receptor (EGFR) T790M "gatekeeper" substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in preclinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo. While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M that spare wild-type EGFR. These findings show the use of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC.
  
  
  CONCLUSIONS
  EGFR-mutant lung cancer patients who respond to currently used EGFR kinase inhibitors invariably develop drug resistance, which is associated with the EGFR T790M resistance mutation in about half these cases. We unexpectedly identified a class of reversible potent inhibitors of EGFR T790M that do not inhibit wild-type EGFR, revealing a promising therapeutic strategy to overcome T790M-associated drug-resistant lung cancers.
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Lily
authors.initials: L
authors.lastname: Shao
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Ye
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.forename: Savita
authors.initials: S
authors.lastname: Ubhayakar
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Valentina
authors.initials: V
authors.lastname: Pirazzoli
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D019540:Area Under Curve; D001483:Base Sequence; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D015151:Immunoblotting; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D019311:Staurosporine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D002227:Carbazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C081021:Go 6976; C571455:WZ4002; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019311:Staurosporine; C059539:midostaurin