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Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies,cetuximab and panitumumab |
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| Authors: | Nayoung Kim Daseul Cho Hyunjin Kim Sujin Kim Young-je Cha Heidi Greulich Adam Bass Hyun-Soo Cho Jeonghee Cho |
| Affiliation: | 1. Department of Nanobiomedical Science, Dankook University, Cheonan, Republic of Korea Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea;2. Department of Nanobiomedical Science, Dankook University, Cheonan, Republic of Korea;3. Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea;4. Broad Institute of Harvard and MIT, Cambridge, MA Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA;5. Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA |
| Abstract: | Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer-derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand-independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF-induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab in vivo and in vitro. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti-EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first-line therapy. |
| Keywords: | epidermal growth factor receptor (EGFR) cetuximab (Erbitux) panitumumab colon cancer EGFR mutation receptor dimerization targeted therapy |