title: Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors.
abstract: OBJECTIVE
  In patients whose lung adenocarcinomas harbor epidermal growth factor receptor (EGFR) tyrosine kinase domain mutations, acquired resistance to the tyrosine kinase inhibitors (TKI) gefitinib (Iressa) and erlotinib (Tarceva) has been associated with a second-site EGFR mutation, which leads to substitution of methionine for threonine at position 790 (T790M). We aimed to elucidate the frequency and nature of secondary EGFR mutations in patients with acquired resistance to TKI monotherapy.
  
  
  METHODS
  Tumor cells from patients with acquired resistance were examined for secondary EGFR kinase domain mutations by molecular analyses.
  
  
  RESULTS
  Eight of 16 patients (50% observed rate; 95% confidence interval, 25-75%) had tumor cells with second-site EGFR mutations. Seven mutations were T790M and one was a novel D761Y mutation found in a brain metastasis. When combined with a drug-sensitive L858R mutation, the D761Y mutation modestly reduced the sensitivity of mutant EGFR to TKIs in both surrogate kinase and cell viability assays. In an autopsy case, the T790M mutation was found in multiple visceral metastases but not in a brain lesion.
  
  
  CONCLUSIONS
  The T790M mutation is common in patients with acquired resistance. The limited spectrum of TKI-resistant mutations in EGFR, which binds to erlotinib in the active conformation, contrasts with a wider range of second-site mutations seen with acquired resistance to imatinib, which binds to ABL and KIT, respectively, in closed conformations. Collectively, our data suggest that the type and nature of kinase inhibitor resistance mutations may be influenced by both anatomic site and mode of binding to the kinase target.
authors.affiliation: Human Oncology and Pathogenesis Program, Thoracic Oncology Service, Varmus Lab, Department of Pathology, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Marissa N
authors.initials: MN
authors.lastname: Balak
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Romel
authors.initials: R
authors.lastname: Somwar
authors.forename: Allan R
authors.initials: AR
authors.lastname: Li
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: Anne
authors.initials: A
authors.lastname: Chiang
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D018628:Gene Dosage; D006801:Humans; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib