Abstract
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.
Highlights
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
EGFR protein is overexpressed in many cancers even without evidence of focused genomic alteration, as observed in many cases of colorectal carcinoma where EGFR kinase domain mutations were found in only 3 out of 224 cases, 1.3% subjected to whole exome sequencing [11,12]
We found that G719S and G724S mutants are oncogenic in the absence of ligand stimulation and effectively respond to cetuximab in vivo and in vitro
Summary
The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. Comparison of nucleotide sequences between the colorectal tumor and normal colon identified an overall mutation rate of 6.7 mutations/Mb including 18,401 somatic nucleotide substitutions, and 983 somatic insertions and deletions of < 37 bases (Figure 1B and Additional file 3: Table S2). Substitution of EGFR G719, the first residue of this motif, to serine, cysteine, or alanine, has been observed in lung adenocarcinomas (~1%), and one G719S mutant and four G724S mutants have been reported in colorectal carcinomas that were sequenced for EGFR (Figure 1C) [18,29] (COSMIC database) These EGFR mutations were found to be mutually exclusive with well known KRAS, BRAF and PIK3CA oncogenic driver mutations, demonstrating their potential role in tumorigenesis (COSMIC database). Colon-cancer derived G719S and G724S mutants are oncogenic and sensitive to cetuximab To determine whether the G724S mutant is oncogenic and to evaluate its pharmacologic sensitivity, we generated this
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