Efficient Blockade of Akt signaling is a determinant factor to overcome resistance to Matuzumab

Molecular Cancer

Research

Cinthya Sternberg¹  Vitor H Almeida¹  Mauricio S Caetano¹  Delano Batista¹  Isabel P Nóbrega¹  Jânio S Mororó¹  Carlos G Ferreira¹  Debora D Meira² 

[1] Coordination of Clinical Research, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil;Coordination of Clinical Research, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil;Departamento de Farmácia, Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM), Espírito Santo, Brazil;

关键词: Matuzumab;    PI3K/Akt pathway;    EGFR;    gynecological cancer;    cervical cancer;    Cetuximab;   

DOI  :  10.1186/1476-4598-10-151

 received in 2011-06-13, accepted in 2011-12-20,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundClinical studies have shown antineoplastic effectiveness of monoclonal antibodies (MAbs) against EGFR for different indications. Several MAbs directed to EGFR were developed recently, such as matuzumab, but there is still lack of information on preclinical data on its combination with chemo-radiation. Thus, the present study intended to examine the molecular pathways triggered by matuzumab alone or associated to chemo-radiotherapy in gynecological cell lines and its impact on cell growth and signaling.ResultsCombination of matuzumab with radiation and cisplatin did not enhance its cytostatic effects on A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in clonogenic assays, when compared to controls. The lack of effect was mediated by persistent signaling through EGFR due to its impaired degradation. In spite of the fact that matuzumab inhibited phosphorylation of EGFR, it had no effect upon cell viability. To analyze which downstream molecules would be involved in the EGFR signaling in the presence of matuzumab, we have tested it in combination with either PD98059 (MAPK inhibitor), or LY294002 (PI3K inhibitor). Matuzumab exhibited a synergic effect with LY294002, leading to a reduction of Akt phosphorylation that was followed by a decrease in A431 and Caski cells survival. The combination of PD98059 and matuzumab did not show the same effect suggesting that PI3K is an important effector of EGFR signaling in matuzumab-treated cells. Nonetheless, matuzumab induced ADCC in Caski cells, but not in the C33A cell line, suggesting that its potential therapeutic effects in vitro are indeed dependent on EGFR expression.ConclusionsMatuzumab combined with chemoradiation did not induce cytotoxic effects on gynecological cancer cell lines in vitro, most likely due to impaired EGFR degradation. However, a combination of matuzumab and PI3K inhibitor synergistically inhibited pAkt and cell survival, suggesting that the use of PI3K/Akt inhibitors could overcome intrinsic resistance to matuzumab in vitro. Altogether, data presented here can pave the way to a rational design of clinical strategies in patients with resistant profile to anti-EGFR inhibitors based on combination therapy.

【 授权许可】

Unknown   
© Meira et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.