Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies, cetuximab and panitumumab

Nayoung Kim, Daseul Cho, Hyunjin Kim, Sujin Kim, Young je Cha, Heidi Greulich, Adam Bass, Hyun Soo Cho, Jeonghee Cho

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusAccepted/In press - 2019 Jan 1

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Epidermal Growth Factor Receptor
Adenocarcinoma
Monoclonal Antibodies
Mutation
Colorectal Neoplasms
Dimerization
Epidermal Growth Factor
Colonic Neoplasms
panitumumab
Cetuximab
Ligands
Antibodies
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, Nayoung ; Cho, Daseul ; Kim, Hyunjin ; Kim, Sujin ; Cha, Young je ; Greulich, Heidi ; Bass, Adam ; Cho, Hyun Soo ; Cho, Jeonghee. / Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies, cetuximab and panitumumab. In: International Journal of Cancer. 2019.
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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.",
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Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies, cetuximab and panitumumab. / Kim, Nayoung; Cho, Daseul; Kim, Hyunjin; Kim, Sujin; Cha, Young je; Greulich, Heidi; Bass, Adam; Cho, Hyun Soo; Cho, Jeonghee.

In: International Journal of Cancer, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Cha, Young je

AU - Greulich, Heidi

AU - Bass, Adam

AU - Cho, Hyun Soo

AU - Cho, Jeonghee

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