title: The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies.
abstract: OBJECTIVE
  A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described.
  
  
  METHODS
  To study acquired resistance to third-generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses.
  
  
  RESULTS
  Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs.
  
  
  CONCLUSIONS
  Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments.
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Niederst
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Haichuan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hillary E
authors.initials: HE
authors.lastname: Mulvey
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Angel R
authors.initials: AR
authors.lastname: Garcia
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Piotrowska
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. jengelman@mgh.harvard.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003062:Codon; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors