Associação Portuguesa de Investigação em Cancro
AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors
AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors
Cetuximab is the only anti-EGFR treatment approved for the treatment of head and neck tumors, however, an insufficient response rates have been reported in HNSCC patients. For this reason, in last years, a new class of anti-EGFR (afatinib and allitinib) with covalent and irreversible action to others members of EGFR family were designed. In our study, we demonstrated the higher efficiency of these irreversible inhibitors when compared to cetuximab. In addition, we found a persistent AKT phosphorylation in resistant cell lines treated with anti-EGFR inhibitors. Isoform-specific gene silencing of AKT by RNA interference restore the sensibility to the both irreversible anti-EGFR inhibitors. In silico analysis of HNSCC patients data, showed high rate of AKT phosphorylation associated with metastatic event such as tumor size and perineural invasion, suggesting that anti-EGFR and anti-AKT therapies combination can offer additive benefits to these patients.
Authors and Affiliations:
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.
Journal: Oncotarget
