Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 146, Issue 8, Pages 2194-2200Publisher
WILEY
DOI: 10.1002/ijc.32499
Keywords
epidermal growth factor receptor (EGFR); cetuximab (Erbitux); panitumumab; colon cancer; EGFR mutation; receptor dimerization; targeted therapy
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Funding
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI15C2353]
- National Research Foundation of Korea (NRF) - Korea government (MEST) [2016R1A2B2011100]
- National Research Foundation of Korea [2016R1A2B2011100] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Somatic mutations of epidermal growth factor receptor (EGFR) occur in similar to 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.
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