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    • It was also shown that of

    2024-03-18

    It was also shown that 15% of crizotinib resistance mechanisms can be due to an amplification of ALK gene while 30% are caused by a variety of secondary mutations (S1206Y, G1202R, L1196M, C1156Y, G1269A, L1152R, F1174L and 1151Tins) in ALK tyrosine kinase. These mutations can modify the conformation of ALK binding site and block the binding of crizotinib. In addition, other mechanisms of resistance to crizotinib include the activation of tyrosine kinase receptors such as EGFR, KRAS, or cKIT (Isozaki et al., 2015). Finally, when it comes to the clinical aspect, several diagnostic methods are used to detect the variants of EML4-ALK, but many guidelines, like those developed in Europe, Japan and US recommended ALK IHC for pre-screening with a mandatory verification of positive results by FISH before using the crizotinib therapy in patients (Tsao et al., 2013). On the other hand, RT-PCR is not an acceptable alternative to FISH to determine patients eligible to undergo ALK inhibitor therapy (Leighl et al., 2014). In addition to the EGFR mutations and EML4-ALK fusion, other mutations involving other genes have been discovered in patients with lung cancer. In routine, there are TKIs for ALK rearrangement, ROS 1 and EGFR mutations. Several trials are currently in progress to develop target therapies for the others mutations: KRAS (32.2%), MET 9-Phenanthrol 14 (4.3%), BRAF (7%), PIK3CA (2%), HER2 (1.7%), amplification of HER2 (0.9%), RET (1%), amplification of MET (2.2%) (Cancer Genome Atlas Research Network, 2014; Rosell and Karachaliou, 2016) (Fig. 3). While ALK rearrangements and EGFR mutations are usually mutually exclusive (Wong et al., 2009), cases of coexistence have been defined and provide a mechanism for TKI resistance. As previously described in part 1 and part 2, ALK fusion was reported to induce resistance to EGFR tyrosine kinase inhibitors (TKIs) (Shaw et al., 2009). Conversely, EGFR mutation is one of the most crucial mechanisms of resistance against ALK-inhibitor. Indeed, the EGFR mutation alone represents 30% of the resistance mechanisms against crizotinib (Isozaki et al., 2015; Drizou et al., 2017). The presence of the fusion EML4-ALK correlates with a wild type EGFR status. However, in 2008, Jussi P Koivunen discovered the first concomitance between the EGFR mutation and the EML4-ALK fusion (Koivunen et al., 2008). This funding gave way to a new therapeutical pathway since the tumor progression depends on the targeted therapy as well as on the mutational status of the both tyrosine kinase receptors (Zhang et al., 2010). Since then, several research studies have been carried out, and nighty seven cases (Fan et al., 2016; Koivunen et al., 2008; Zhang et al., 2010; Kuo et al., 2010; Popat et al., 2011; Tiseo et al., 2011b; Sasaki et al., 2011; Tanaka et al., 2012; Wang et al., 2012; Lee et al., 2012; Rossing et al., 2013; Santelmo et al., 2013; Chen et al., 2013; Miyanaga et al., 2013; Boland et al., 2013; Baldi et al., 2014; Yang et al., 2014; Jürgens et al., 2014; Cabillic et al., 2014; Lee et al., 2016; Kim et al., 2014; Chiari et al., 2014; Zhao et al., 2015; Zhou et al., 2015; Xu et al., 2015; Sahnane et al., 2016; Marino et al., 2015; Won et al., 2015; Kim et al., 2016; Camidge et al., 2010; Ulivi et al., 2016; Sweis et al., 2016; Wang et al., 2014; Xia et al., 2013) representing a concomitance between the EML4-ALK fusion and the EGFR mutation have been reviewed in this current review (Table 1). In all the reviewed studies, the coexistence of ALK rearrangement and EGFR mutations have never exceeded 6%. This was confirmed by the studies of Shaw and Zhang (Shaw et al., 2009; Zhang et al., 2010) that found out that this concomitance was usually between 0 and 8%. The mutational status of EGFR was been reported for 94 cases. However, 72 cases had an activating mutation associated with an increased sensitivity to gefitinib and erlotinib (EGFR-TKI) with 53% (50/94) for deletion in exon 19 and 25.5% (24/94) for the missense mutation L858R in exon 21. Furthermore 5 cases had a missense mutations in exon 18 (1 L718P and 4 G719X), 2 cases with alterations in exon 19 (1 K757L and 1 A767-V769dupASV), 3 cases had alterations in exon 20 (1 insertion, 1 S768 and 1 R803W), 7 cases had a missense mutation in exon 21 (4 L861Q, 2 L862 and 1 E868R), 1 case had a polymorphism in exon 23 and 2 cases presenting a double mutation (1 L858R + T790M, 1 del19 + A750P) (Table 2).