Anastrozole br Conclusion br Introduction Lung cancer is

Conclusion
Introduction Lung cancer is the principal cause of death by cancer and the third most common cancer worldwide (Sorber et al., 2016). Lung cancer has two main types: small cell carcinomas (approximately 20%) and non-small cell lung cancers (NSCLC) (about 80%) (Fan et al., 2016). NSCLC are divided into three subgroups: the Squamous cell carcinoma (approximately 40%), large cell carcinoma (About 10%), and adenocarcinoma (30%). Adenocarcinomas represent more than 50% of all lung cancers (Bhattacharjee et al., 2001). Roughly 90% of lung cancer are due to the use of tobacco products (Gankhuyag et al., 2016), not only the active consumption of tobacco, but also passive inhalation of smoke, called secondary flow, exhaled by active smokers which increase the cancer risk in lungs (Office on Smoking and Health (US), 2006). Other factors, also known as professional factors, like exposure to cadmium, arsenic (Chen et al., 2016; Huff et al., 2016) and other substances were shown to cause lung cancer in Humans. However, recent growing evidence (El-Telbany and Ma, 2012; Kitamura et al., 2008; Yokota et al., 2003) reported that several genetic alterations may also be responsible for its development. Although the NSCLC can be treated by many therapies (surgery, radiation therapy, chemotherapy…), targeted therapy is the most popular treatment used by physicians nowadays (Mamdani et al., 2015). It is based on the mutational status of several genes, plus mainly epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) fusion gene, c-ros oncogene 1 receptor tyrosine kinase (ROS1) and B-Raf (BRAF) (Chan and Hughes, 2015). In fact, this treatment has proven to efficiently achieve an initial stable disease in lung cancer patients. The molecular alterations at both EGFR and ALK Anastrozole have been independently discovered and are mutually exclusive (Wong et al., 2009). However, in 2008, Koivunen and his team discovered the first case of concurrence between the mutation of EGFR and the EML4-ALK fusion gene (Koivunen et al., 2008). This led to a series of studies reporting many cases involving this co-mutation. This review is designed to shed light on the literature published since 2008, which represent the clinicopathological characteristics of cases with coexistence of EGFR mutations and EML4-ALK fusion. The EGFR gene is located on chromosome 7, encodes a tyrosine kinase receptor containing a single polypeptide chain of 1210 aminoacids, and is expressed on the surface of the majority of normal cells (Hodoglugil et al., 2013). The receptor consists of three regions, the extracellular ligand binding region, the intracellular region with tyrosine kinase activity and a transmembrane region with a single hydrophobic anchor sequence (Lemmon and Schlessinger, 2010) (Fig. 1). The EGFR gene encodes a transmembrane receptor tyrosine kinase, that binds many ligands of the EGF receptor. This binding triggers its activation and the autophosphorylation of the intracellular end, stimulating the downstream signaling pathways, like the Ras/Raf/mitogen-activated protein kinase (MAPK) and PI3K-AKT ones, thus regulating the proliferation tumor, its ability for invasion, resistance to apoptosis and its neo-angiogenesis (Seshacharyulu et al., 2012; Maramotti et al., 2016). Mutations affecting the EGFR are localized around the ATP-binding site of the 4 tyrosine kinase domains of the 18, 19, 20 and 21 exons (Antonicelli et al., 2013). The most common ones (80–90%) are the short in-frame deletions in the LREA motif of exon 19 and the point mutation L858R (Shi et al., 2014; Lynch et al., 2004). This mutation is the result of the substitution of T by C in the exon 21, inducing the substitution of leucine by arginine at codon 858 (Sequist et al., 2007; Ladanyi and Pao, 2008). The insertions in exon 20 and substitutions at codon 719 in exon 18 are also associated to EGFR activation but represent only 5% of all EGFR mutations (Sequist et al., 2007; Ladanyi and Pao, 2008).