Article (Scientific journals)
Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in bypassing this resistance.
Rebucci, Magali; Peixoto, Paul; Dewitte, Amelie et al.
2011In International Journal of Oncology, 38 (1), p. 189-200
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Abstract :
[en] EGFR is frequently overexpressed in head and neck squamous cell cancer (HNSCC). Cetuximab is a monoclonal antibody designed to interact with EGFR, block its activation, reduce the downstream signaling pathways and induce EGFR internalization. This study aims to investigate the role of the EGFR signaling pathway and EGFR internalization in a cetuximab-resistant cell line and to propose a new therapeutic strategy to optimize treatment of HNSCC. The HNSCC cell line, CAL33 was sensitive to gefitinib but resistant to cetuximab. Cetuximab induces an unexpected EGFR phosphorylation in CAL33 cells similarly to EGF but this EGFR activation does not trigger EGFR internalization/degradation, the process currently implicated in the response to cetuximab. Cetuximab inhibits ERK and AKT phosphorylation in cetuximab-sensitive A431 cells, whereas the level of AKT phosphorylation is unmodified in cetuximab-resistant cells. Interestingly, CAL33 cells harbor a PIK3CA mutation. The treatment of CAL33 cells with PI3K inhibitor and cetuximab restores the inhibition of AKT phosphorylation and induces growth inhibition. Our results indicate that EGFR internalization is impaired by cetuximab treatment in CAL33 cells and that the AKT pathway is a central element in cetuximab resistance. The combination of cetuximab with a PI3K inhibitor could be a good therapeutic option in PIK3CA-mutated HNSCC.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rebucci, Magali
Peixoto, Paul 
Dewitte, Amelie
Wattez, Nicole
De Nuncques, Marie*-Adeline
Rezvoy, Nicolas
Vautravers-Dewas, Claire
Buisine, Marie*-Pierre
Guerin, Eric
Peyrat, Jean*-Philippe
Lartigau, Eric
Lansiaux, Amelie
Language :
English
Title :
Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in bypassing this resistance.
Publication date :
2011
Journal title :
International Journal of Oncology
ISSN :
1019-6439
eISSN :
1791-2423
Publisher :
DA Spandidos, Athens, Greece
Volume :
38
Issue :
1
Pages :
189-200
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 03 March 2011

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