Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance

  • Authors:
    • Magali Rebucci
    • Paul Peixoto
    • Amélie Dewitte
    • Nicole Wattez
    • Marie-Adeline De Nuncques
    • Nicolas Rezvoy
    • Claire Vautravers-Dewas
    • Marie-Pierre Buisine
    • Eric Guerin
    • Jean-Philippe Peyrat
    • Eric Lartigau
    • Amélie Lansiaux
  • View Affiliations

  • Published online on: January 1, 2011     https://doi.org/10.3892/ijo_00000838
  • Pages: 189-200
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Abstract

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.

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January 2011
Volume 38 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Rebucci M, Peixoto P, Dewitte A, Wattez N, De Nuncques M, Rezvoy N, Vautravers-Dewas C, Buisine M, Guerin E, Peyrat J, Peyrat J, et al: Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance. Int J Oncol 38: 189-200, 2011.
APA
Rebucci, M., Peixoto, P., Dewitte, A., Wattez, N., De Nuncques, M., Rezvoy, N. ... Lansiaux, A. (2011). Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance. International Journal of Oncology, 38, 189-200. https://doi.org/10.3892/ijo_00000838
MLA
Rebucci, M., Peixoto, P., Dewitte, A., Wattez, N., De Nuncques, M., Rezvoy, N., Vautravers-Dewas, C., Buisine, M., Guerin, E., Peyrat, J., Lartigau, E., Lansiaux, A."Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance". International Journal of Oncology 38.1 (2011): 189-200.
Chicago
Rebucci, M., Peixoto, P., Dewitte, A., Wattez, N., De Nuncques, M., Rezvoy, N., Vautravers-Dewas, C., Buisine, M., Guerin, E., Peyrat, J., Lartigau, E., Lansiaux, A."Mechanisms underlying resistance to cetuximab in the HNSCC cell line: Role of AKT inhibition in bypassing this resistance". International Journal of Oncology 38, no. 1 (2011): 189-200. https://doi.org/10.3892/ijo_00000838