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Genetic mapping and pharmacologic treatments of NSCLC: a review of the literature

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Abstract

Despite recent advances in medicine, lung cancer continues to be the most common cause of cancer-related deaths. Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Researchers have identified epidermal growth factor receptor (EGFR) mutations that increase the risk for lung cancer in smokers and non-smokers. New pharmacological therapies are aimed at suppressing these oncogene and decreasing the rate of metastasis in certain types of lung cancers. These findings can be useful in not only lung cancer therapies but also other types of cancers. In this review, we provide a brief overview regarding the biology of epidermal growth factor receptor and the development of EGFR inhibitors for the treatment of NSCLC.

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Introduction Worldwide and in the United States, lung cancer is the most common cause of cancer-related deaths. Lung cancer accounts for 28% of cancer deaths in men and 26% of cancer deaths in women (American Cancer Society, 2012). Lung cancer surpassed breast cancer as the leading cause of cancer deaths in women in the late 1980’s and now almost twice as many women die of lung cancer as breast cancer (Siegel, 2011). Non-small-cell lung cancers (NSCLC), account for 85% of all lung cancers. Although chemotherapy has advanced in the treatment of NSCLC, the prognosis is still poor (Smith, 2004). As a class, NSCLC are relatively insensitive to chemotherapy and radiation therapy compared to small-cell lung cancer (SCLC). The 5-year survival rate for lung cancer is only 15% (National Cancer Institute, 2012). The high mortality rate of lung cancer is largely related to the advanced state of the disease at the time of diagnosis. Lung adenocarcinomas often begins in the outer part of the lung, well-known symptoms of lung cancer such as chronic cough and hemoptysis may be less common until the later stages of the disease. Early symptoms like fatigue, mild shortness of breath and myalgia are usually overlooked. The leading cause of lung cancer continues to be cigarette smoking; however, roughly 10% to 15% of lung cancer patients in the United States

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have no history of smoking (Wakalle, 2007). National prevention efforts continue to focus on smoking cessation; however, the percentage of current smokers in the United States has not changed since 2004, after a significant gradual decline from 1997 (Barnes, 2010). Other important risk factors for the development of lung cancer include environmental exposure to tobacco smoke (second hand smoke), radon gas, occupational carcinogens like asbestos, and pre-existing nonmalignant lung disease. The Environmental Protection Agency has issued specific recommendations to reduce and mitigate cancer caused by environmental exposure. In the last decade there have been small but real advances in lung cancer therapy focusing on lung cancer histology and gene mapping. The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of patients with metastatic disease (Pao, 2011). In particular, subgroups of adenocarcinoma (type of NSCLC) can be defined by specific mutations in gene encoding components of epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K). EGFR is a tyrosine kinase that participates in the regulations of cellular homeostasis. Following ligand binding, EGFR stimulates a series of reactions in a cascade that influences cell proliferation, apoptosis, migration, survival and complex cellular process like tumorigenesis.

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The epidermal growth factor receptor (EGFR; Erb-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factors family (EGF-family) of extracellular protein ligands (Herbst, 2004). The EGFR is a member of the ErbB family of receptors, a subfamily of four