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.

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.

• Authors: Jeonghee Cho, Adam J Bass, Michael S Lawrence, Kristian Cibulskis, Ahye Cho, Shi-Nai Lee, Mai Yamauchi, Nikhil Wagle, Panisa Pochanard, Nayoung Kim, Angela Kj Park, Jonghwa Won, Hyung-Suk Hur, Heidi Greulich, Shuji Ogino, Carrie Sougnez, Douglas Voet, Josep Tabernero, Jose Jimenez, Jose Baselga, Stacey B Gabriel, Eric S Lander, Gad Getz, Michael J Eck, Woong-Yang Park, Matthew Meyerson
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 141 (Jun 04 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24894453 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors
• Cetuximab

Topics

• Adenocarcinoma (drug therapy, genetics, pathology)
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Cetuximab
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors, chemistry, genetics, metabolism)
• Gene Expression
• High-Throughput Nucleotide Sequencing
• Humans
• Mutation
• Protein Kinase Inhibitors (therapeutic use)
• Protein Multimerization
• Protein Structure, Tertiary