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    • These mutations induce the gene auto activation

    2023-01-16

    These mutations induce the gene auto-activation in 10–40% of adenocarcinomas, triggering the EGFR-signaling pathway in the absence of ligand. That leads to an uncontrolled acceleration of cell proliferation, survival and anti-apoptotic signals (Couraud et al., 2012). The frequency of these mutations is significantly increased among never smoker patients, (Asians 30–50% against 10–15% of Caucasians) and women (Shi et al., 2014; Couraud et al., 2012; Shigematsu et al., 2005). These alterations in tyrosine kinase receptors inspired the development of the targeted therapy as we know it, creating treatments by tyrosine kinase inhibitors (TKI). Gefitinib and erlotinib were the first two inhibitors to target the tyrosine kinase domain of the EGFR. They both showed promising results in patients with NSCLC previously treated with chemotherapy (Antonicelli et al., 2013). These novel therapies inhibit cell growth and are cytostatic in ID-8 synthesis to conventional chemotherapy, called cytotoxic. Nevertheless, some EGFR-mutated patients can develop acquired resistance to this kind of therapy. Studies have showed that 50% of all acquired resistance on NSCLs are T790M point mutation in exon 20 of EGFR gene. Other mutations on the same gene (L747S, 761Y, T854A) have also been reported as secondary mechanism of resistance to EGFR TKIs These findings enabled the development of a second-generation TKIs capable of overcoming the T790M resistance mechanism (Engelman and Janne, 2008; Bean et al., 2008; Balak et al., 2006). There are other mechanisms of acquired resistance such as MET gene amplification, EML4-ALK fusion and some mutations in genes involved in the same EGFR pathway (PIK3CA, KRAS, BRAF…) (Okudela et al., 2007). ALK gene is located on chromosome 2p23 and encodes for a tyrosine kinase receptor of the superfamily of insulin receptors (Pulford et al., 1997). The ALK is overexpressed during embryogenesis to ensure a proper neurodevelopment (Roskoski, 2013). ALK is a crucial regulator of cell survival and growth pathways, including the mitogen extracellular kinase (MEK)-extracellular signal regulated kinase (ERK) and canonical phosphatidylinositol 3-kinase (PI3K)-AKT pathways. The inhibition of ALK usually results in cell growth arrest and apoptosis (Koivunen et al., 2008; Katayama et al., 2011). Most of the alterations affecting the ALK gene and causing an oncogenesis are translocations and fusion with other genes, amplification and point mutations (Mosse et al., 2009). The first mutation of ALK Linked to NSCLC was discovered in 2007 and it was a translocation and fusion with the EML4 gene (Echinoderm microtubule-associated protein like 4), this mutation affects 4 to 6% of adenocarcinomas (Soda et al., 2007). Both ALK and EML4 genes are localized in the short arm of chromosome 2p, separated by 12pb, but have an opposite orientation (Koivunen et al., 2008). In patients with NSCL, their fusion is generally due to an inversion in the chromosome 2p which results in the binding of the N-terminal domain of EML4 with the tyrosine kinase domain of ALK (Fig. 2). This leads to a constitutive activation of the protein and signaling pathways downstream controlling the proliferation and cell survival (Soda et al., 2007). Different variants of EML4-ALK have been described. They may differ following the EML4 combinations that always merge with the same tyrosine kinase domain of ALK, but their clinical significance still remains unknown (Takeuchi et al., 2008). The ALK rearrangement is mainly affecting the non-smokers, women, youngsters and patients with a distinct clinicopathological features including an adenocarcinoma background (Tiseo et al., 2011a). The research involving the EML4-ALK combination led to developing and adopting an efficient lung cancer treatment: the crizotinib, an ALK tyrosine kinase inhibitor (Kwak et al., 2010). Isozaki H et al. demonstrated that ALK-positive NSCLC patients treated with crizotinib presented a longer Progression-free survival (10.9 months) when compared to their counterparts treated with standard chemotherapy (7.0 months) in advanced and metastatic status (Isozaki et al., 2015). As for the Objective response rates, they were 74% and 45% respectively (Solomon et al., 2014). However, the efficiency of the ALK-TKIs can be relapsed by different resistance mechanisms.