EGFR Targeted Therapy

EGFR Targeted Therapy: Introduction

The EGFR, also known as ErbB1, is a 170 kDa protein belonging to the four-member ErbB family of transmembrane tyrosine kinase growth factor receptors. Binding by a number of ligands induces conformational alterations in the single chain receptor, allowing dimerization or oligomerization with other EGFR molecules or other members of the ErbB family. Multimer formation leads to asymmetric autophosphorylation of a tyrosine residue on the intracellular portion of one of the molecules, allowing the receptor to recruit docking proteins and signal transduction molecules. The resulting cascades, involving the Ras/mitogen-activating protein (MAP) kinase pathway, the Phosphoinositide-3 kinase (PI3K)/Akt pathway, Src family kinases, and signal transducers and activator of transcription (STAT) proteins, result in upregulation of mitogenic, antiapoptotic, angiogenic, and pro-invasive cellular mechanisms. EGFR is expressed or overexpressed in many cancers, Which make it a useful target for targeted therapies of cancers, such as breast cancer, colorectal cancer, head and neck cancer, non-small-cell lung cancer, ovivian cancer and pancreatic cancer.

EGFR overexpression is found in at least 50% of cases of (triple-negative breast cancer) TNBC, which is a higher expression rate than the rates seen in other breast cancer subtypes. Because of the high rate of overexpression of EGFR in TNBC, EGFR inhibitors are among the targeted agents being developed for treatment of TNBC.
Patients with EGFR positive (inflammatory breast cancer) IBC have a worse 5-year overall survival rate than patients with EGFR-negative tumors, and EGFR expression in IBC is associated with an increased risk of recurrence. Because conventional chemotherapy regimens are not sufficient for the treatment of IBC, new therapies for IBC are needed. Among the potential candidates are therapies that target the EGFR pathway.

Colorectal cancer (CRC) remains a formidable health burden worldwide, with up to 50% of patients developing metastases during the course of their disease. This group of colorectal cancer patients, characterized by the worst prognosis, has been extensively investigated to improve their life expectancy. Main efforts, focused on the epidermal growth-factor receptor (EGFR), which plays a pivotal role in colorectal cancer pathogenesis, have led to the development and introduction in clinical practice of specific targeted therapies (ie, monoclonal antibodies).

Head and neck squamous cell cancer is the sixth most common neoplasm worldwide, with approximately 600,000 patients newly diagnosed each year. Over the past 30 years, patients with recurrent and/or metastatic head and neck squamous cell cancer have had a poor prognosis.More than 50% of newly diagnosed patients do not achieve complete remission, and approximately 10% relapse with metastasis to distant organs. Therefore, research focused on gaining a better understanding of this disease and on the development of novel treatment strategies is required. Targeted therapy is a appropriate choice.

Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men and women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10–15% inWestern countries, epidermal growth factor receptor (EGFR) mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, or afatinib is recommended.

Advanced ovarian cancer carries a grim prognosis and development of targeted therapies to improve outcomes has become an active area of research in this disease. The epidermal growth factor receptor (EGFR) has shown to be overexpressed in ovarian cancer and there have been several clinical trials evaluating anti-EGFR therapies in ovarian cancer. Unfortunately, the drugs have shown minimal efficacy and more recent work has now focused on identifying mechanisms of resistance and alternative ways of targeting these pathways.

Pancreatic cancer is the fourth leading cause of cancer related death. The difficulty in detecting pancreatic cancer at an early stage, aggressiveness and the lack of effective therapy all contribute to the high mortality. In the last two decades, many laboratories have focused effort on characterizing the molecular alterations that are present in pancreatic cancer. Much attention has been paid to the role of growth factors and growth factor receptors in pancreatic cancer. They have been implicated in carcinogenesis by affecting a variety of functions including cell proliferation, cell invasion and metastasis, angiogenesis, immune responsiveness and extracellular matrix formation. A number of growth factors and their receptors have been shown to play an important role in pancreatic cancer, including the epidermal growth factor (EGF) family. This family of ligands and receptors plays an important role in the pathogenesis of pancreatic ductal carcinoma and contributes to its aggressiveness.