title: Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab.
abstract: BACKGROUND
  Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear.
  
  
  RESULTS
  We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors.
  
  
  CONCLUSIONS
  The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02115, USA. jeong.cho@skku.edu.
authors.forename: Jeonghee
authors.initials: J
authors.lastname: Cho
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.forename: Ahye
authors.initials: A
authors.lastname: Cho
authors.forename: Shi-Nai
authors.initials: SN
authors.lastname: Lee
authors.forename: Mai
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.forename: Panisa
authors.initials: P
authors.lastname: Pochanard
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Angela Kj
authors.initials: AK
authors.lastname: Park
authors.forename: Jonghwa
authors.initials: J
authors.lastname: Won
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Hur
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.forename: Douglas
authors.initials: D
authors.lastname: Voet
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Jose
authors.initials: J
authors.lastname: Jimenez
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab