Colorectal adenocarcinoma-derived EGFR mutants are oncogenic and sensitive to EGFR-targeted monoclonal antibodies, cetuximab and panitumumab.
Adenocarcinoma
/ drug therapy
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Cetuximab
/ pharmacology
Colorectal Neoplasms
/ drug therapy
Dimerization
ErbB Receptors
/ genetics
HT29 Cells
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Targeted Therapy
Mutation
NIH 3T3 Cells
Panitumumab
/ pharmacology
Xenograft Model Antitumor Assays
EGFR mutation
cetuximab (Erbitux)
colon cancer
epidermal growth factor receptor (EGFR)
panitumumab
receptor dimerization
targeted therapy
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 04 2020
15 04 2020
Historique:
received:
23
12
2018
revised:
08
05
2019
accepted:
29
05
2019
pubmed:
11
7
2019
medline:
19
5
2020
entrez:
11
7
2019
Statut:
ppublish
Résumé
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.
Substances chimiques
Antineoplastic Agents, Immunological
0
Panitumumab
6A901E312A
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Cetuximab
PQX0D8J21J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2194-2200Informations de copyright
© 2019 UICC.
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