Methylation as a response modulation mechanism to EGFR inhibitors in Head and Neck Carcinoma

Abstract

Head and neck cancer (HNSCC) is a disease with high incidence and mortality mainly affecting the oral cavity, pharynx and larynx, it is considered to be the fth most common cancer site worldwide and is associated with low survival rates. The poor survival rate has been ascribed to a high frequency of locoregional recurrences, and the occurrence of second primary tumors and deaths due to comorbidity, mostly to the fact that the majority of patients present advanced stages at the time of diagnosis.The carcinogenesis process comprises multiple steps in which several genetic and epigenetic alterations are accumulated. Activation of proto-oncogenes and inactivation of tumor suppressor genes are the major molecular alterations involved in carcinogenesis. In addition, epigenetic changes can alter the expression of critical genes important in the development of a variety of cancers. Furthermore, the presence of mutations in the phosphorylation domain of protein kinases have been associated to the development of many solid tumors, including HNSCC.Therapies targeting inhibition of multiple points along the signal transduction pathways are potential new approaches in the treatment of cancer. The signaling pathway of the epidermal growth factor receptor (EGFR) is commonly activated in HNSCC and represents a target for therapy. EGFR is a transmembrane tyrosine kinase receptor that plays a central role in regulating cell division and death. Overexpression of the receptor, of its phosphorylated form or any paths occurs mostly in epithelial tumors, including HNSCC, and correlates with poor prognosis and resistance to anticancer therapies. Tyrosine kinase inhibitors (TKIs) are a class of anticancer agents that act by competing with the binding site of the catalytic domain of several oncogenic tyrosine kinases. This inhibitory effect is key towards blocking the cellular replication, survival, metastasis and angiogenesis of cancer cells. Among the different anti-EGFR agents, such as tyrosine kinase inhibitors and monoclonal antibodies (mAbs), the reversible inhibitor Cetuximab is the only approved for HNSCC treatment. However, treatment with these reversible tyrosine kinase inhibitors produces objective responses in only a small subset of patients. Despite an initial positive response, these patients often develop or acquire secondary resistance to the inhibitors, leading to relapse after several months. Thus, the resistance to anti-EGFR reversible inhibitors has emerged as an important clinical problem, making irreversible inhibitors studies essential for HNSCC tumors, such as clinical trials with Afatinibe and Allitinibe.Based on this, the aim of this project is to increase the knowledge in sensitivity and cellular resistance to EGFR inhibitor treatment, and also try to correlate the methylation status with this response by characterizing the in vitro profile of these characteristics in several HNSCC cell lines. Thus, this project presents an emerging and current topic, being a clear example of translational research that will not only help to increase the knowledge of HNSCC but also with practical implications and benefits in clinical care of these patients.