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

Molecular Cancer

Short Communication

Michael J Eck¹  Jose Baselga²  Mai Yamauchi³  Shuji Ogino³  Panisa Pochanard⁴  Nikhil Wagle⁴  Jeonghee Cho⁵  Adam J Bass⁶  Matthew Meyerson⁷  Heidi Greulich⁸  Jose Jimenez⁹  Josep Tabernero^1,10  Hyung-Suk Hur^1,11  Jonghwa Won^1,11  Shi-Nai Lee^1,11  Nayoung Kim^1,12  Ahye Cho^1,12  Woong-Yang Park^1,12  Angela K J Park^1,12  Kristian Cibulskis^1,13  Douglas Voet^1,13  Michael S Lawrence^1,13  Carrie Sougnez^1,13  Eric S Lander^1,13  Stacey B Gabriel^1,13  Gad Getz^1,13 

[1] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 02115, Boston, MA, USA;Department of Pathology, Harvard Medical School, 02115, Boston, MA, USA;Department of Cancer Biology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Samsung Genome Institute, Samsung Medical Center, 135-967, Seoul, Republic of Korea;Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, 135-967, Seoul, Republic of Korea;Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;The Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;The Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Pathology, Harvard Medical School, 02115, Boston, MA, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, MA, USA;The Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 02115, Boston, MA, USA;Memorial Sloan-Kettering Cancer Center, 10065, New York, NY, USA;Molecular Pathology Laboratory, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain;Oncology team, Mogam Biotechnology Research Institute, 446-799, Yongin, Republic of Korea;Samsung Genome Institute, Samsung Medical Center, 135-967, Seoul, Republic of Korea;Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, 135-967, Seoul, Republic of Korea;The Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;

关键词: Epidermal Growth Factor Receptor;    Cetuximab;    Epidermal Growth Factor Receptor Mutation;    Epidermal Growth Factor Receptor Gene;    Epidermal Growth Factor Receptor Signaling;   

DOI  :  10.1186/1476-4598-13-141

 received in 2014-02-07, accepted in 2014-05-23,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundInhibition 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.FindingsWe 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.ConclusionThe 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.

【 授权许可】

CC BY   
© Cho et al.; licensee BioMed Central Ltd. 2014