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.
Bibliographical noteFunding Information:
Key words: epidermal growth factor receptor (EGFR), cetuximab (Erbitux), panitumumab, colon cancer, EGFR mutation, receptor dimerization, targeted therapy Abbreviations: CRC: colorectal cancer; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; WT: wild-type Additional Supporting Information may be found in the online version of this article. Conflict of interest: No conflict of interest for any of the authors. Grant sponsor: The Ministry of Health & Welfare, Republic of Korea; Grant number: HI15C2353; Grant sponsor: The National Research Foundation of Korea (NRF); Grant number: 2016R1A2B2011100 N.K., D.C. and H.K. contributed equally to this work DOI: 10.1002/ijc.32499 History: Received 23 Dec 2018; Accepted 29 May 2019; Online 10 Jun 2019 Correspondence to: Jeonghee Cho, Department of Nanobiomedical Science, Dankook University, 119 Dandae-ro, Cheonan 31116, Republic of Korea, Tel.: 82-41-550-1172, E-mail: jeonghee. email@example.com
The authors would like to thank to Joshua Francis for constructive criticism of the manuscript. This work was in part supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2353; J.C.) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2016R1A2B2011100; J.C.).
© 2019 UICC
All Science Journal Classification (ASJC) codes
- Cancer Research