Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab

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• 作者：Jeonghee Cho (5) (6) (7) (8)
  Adam J Bass (5) (6) (9)
  Michael S Lawrence (9)
  Kristian Cibulskis (9)
  Ahye Cho (7) (8)
  Shi-Nai Lee (10)
  Mai Yamauchi (5)
  Nikhil Wagle (5) (6)
  Panisa Pochanard (5) (6)
  Nayoung Kim (7) (8)
  Angela KJ Park (7) (8)
  Jonghwa Won (10)
  Hyung-Suk Hur (10)
  Heidi Greulich (11) (5) (9)
  Shuji Ogino (5)
  Carrie Sougnez (9)
  Douglas Voet (9)
  Josep Tabernero (12)
  Jose Jimenez (13)
  Jose Baselga (14)
  Stacey B Gabriel (9)
  Eric S Lander (9)
  Gad Getz (9)
  Michael J Eck (15) (16)
  Woong-Yang Park (7) (8)
  Matthew Meyerson (16) (5) (6) (9)
  
  5. Department of Medical Oncology ; Dana-Farber Cancer Institute ; Boston ; MA ; 02115 ; USA
  6. Center for Cancer Genome Discovery ; Dana-Farber Cancer Institute ; Boston ; MA ; 02115 ; USA
  7. Samsung Genome Institute ; Samsung Medical Center ; Seoul ; 135-967 ; Republic of Korea
  8. Samsung Advanced Institute for Health Sciences and Technology ; SungKyunKwan University ; Seoul ; 135-967 ; Republic of Korea
  9. The Broad Institute of MIT and Harvard ; Cambridge ; MA ; 02142 ; USA
  10. Oncology team ; Mogam Biotechnology Research Institute ; Yongin ; 446-799 ; Republic of Korea
  11. Department of Medicine ; Brigham and Women鈥檚 Hospital ; Harvard Medical School ; Boston ; MA ; 02115 ; USA
  12. Molecular Pathology Laboratory ; Vall d鈥橦ebron University Hospital ; Universitat Aut貌noma de Barcelona ; Barcelona ; Spain
  13. Memorial Sloan-Kettering Cancer Center ; New York ; NY ; 10065 ; USA
  14. Department of Cancer Biology ; Dana-Farber Cancer Institute ; Boston ; MA ; 02115 ; USA
  15. Department of Biological Chemistry and Molecular Pharmacology ; Harvard Medical School ; Boston ; MA ; 02115 ; USA
  16. Department of Pathology ; Harvard Medical School ; Boston ; MA ; 02115 ; USA
  
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：402 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

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. Findings 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. Conclusion 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.