Associação Portuguesa de Investigação em Cancro
AKT modula a resposta in vitro de células de HNSCC a inibidores irreversíveis de EGFR
AKT modula a resposta in vitro de células de HNSCC a inibidores irreversíveis de EGFR
O cetuximab é único tratamento anti-EGFR aprovado para o tratamento dos tumores de cabeça e pescoço, porém têm apresentado insuficientes taxas de respostas devido aos mecanismos de resistência. Diante disso, novas abordagem terapêuticas emergiram neste cenário, sendo representada pelos inibidores de EGFR, afatinib e allitinib, que possuem uma ligação covalente e irreversível ao EGFR e outros membros desta família. Em nosso estudo demonstramos a maior eficiência destes inibidores irreversíveis, comparados ao cetuximab. Além disso, a persistente fosforilação de AKT foi encontrada nas linhagens celulares resistentes a esta nova modalidade terapêutica. O silenciamento gênico da principal isoforma de AKT, restabeleceu a sensibilidade aos inibidores irreversíveis. De forma translacional, em nossa análise in silico, encontramos altas taxas de fosforilação de AKT associadas a eventos metastáticos como o tamanho tumoral e a invasão perineural indicando que a associação entre as terapias anti-EGFR e anti-AKT podem se revelar promissoras no tratamento de pacientes portadores de tumores de cabeça e pescoço.
Autores e Afiliações:
Renato José Silva-Oliveira1; Matias Melendez1, Olga Martinho1,2,3, Maicon F. Zanon1, Luciano de Souza Viana1,4, André Lopes Carvalho1, Rui Manuel Reis1,2,3
1 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil;
2 Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal;
3 ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal;
4 Department of Medical Oncology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
Abstract:
Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and AKT1 gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success.
Revista: Oncotarget