Oncotarget

Research Papers:

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors

Renato José Silva-Oliveira, Matias Melendez, Olga Martinho, Maicon F. Zanon, Luciano de Souza Viana, André Lopes Carvalho and Rui Manuel Reis _

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Oncotarget. 2017; 8:53288-53301. https://doi.org/10.18632/oncotarget.18395

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Abstract

Renato José Silva-Oliveira1, Matias Melendez1, Olga Martinho1,2,3, Maicon F. Zanon1, Luciano de Souza Viana1,4, André Lopes Carvalho1 and Rui Manuel Reis1,2,3

1Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil

2Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal

3ICVS/3B’s-PT Government Associate Laboratory, Braga, Portugal

4Department of Medical Oncology, Barretos Cancer Hospital, Barretos, Brazil

Correspondence to:

Rui Manuel Reis, email: ruireis.hcb@gmail.com

Keywords: HNSCC, anti-EGFR, anti- AKT, AKT1, resistance

Received: July 20, 2016    Accepted: May 16, 2017    Published: June 07, 2017

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.


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