During tumorigenesis the immune system exerts

During tumorigenesis, the immune system exerts additional pressure that likely contributes to the selection of certain tumor clones. Hence, the immune system may be a factor in selecting tumor purchase LY2606368 with a defined metabolic state (Villalba et al., 2013; Catalán et al., 2015). Notably, ERK5 is an important factor in both tumor immune evasion and tumor cell metabolism (Charni et al., 2009; Charni et al., 2010). The fact that ERK5 is involved in several phenomena described here, namely tumor cell evasion, metabolism and antioxidant response, shows that several phenomena converge to generate a specific phenotype in a clinical tumor.
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Author Contributions
Acknowledgements All our funders are public or charitable organizations. This work was supported by the program “Chercheur d\'avenir” from the Region Languedoc-Roussillon (09-13195) (MV), a scientific program from the “Communauté de Travail des Pyrénées” (CTPP5/12 to MV), the charities CIEL, L\'Un pour l\'Autre and Ensangble (09/2013) (MV), a grant from the European Community Program SUDOE (CLiNK SOE2/P1/E341 to MV), an AOI from the CHU Montpellier (No. 221826) (GC and MV), a grant from Fondation de France (0057921) and fellowships from the Higher Education Commission, Pakistan (MGR and AK) and Ministère de l\'Enseignement Supérieur et de la Recherche (MESR) (DNV). FACs analysis was performed at the platform Montpellier Rio Imaging (MRI). The collection of clinical data and samples (HEMODIAG_2020) at the CHRU Montpellier was supported by funding from Région Languedoc Roussillon. We thank Dr. Robert A. Hipskind for English correction of this manuscript.
Introduction The anaplastic lymphoma kinase (ALK) fusion oncogene caused by chromosomal rearrangement has been observed in a variety of human malignancies, including ALK-rearranged non-small cell lung cancer (NSCLC), which was identified in 2007 (Soda et al., 2007). ALK gene rearrangement results in the constitutive expression and activation of an ALK fusion protein, which has been shown to strongly drive oncogenesis. To target ALK-rearranged NSCLC, the oral ALK and v-ros avian ur2 sarcoma virus oncogene homolog 1 (ROS1) inhibitor crizotinib have been used. Two randomized phase 3 studies of crizotinib showed significantly longer progression-free survival (PFS; 7.7months vs 3.0months in the second-line study and 10.9months vs 7.0months in the first-line study) and higher overall response rate [ORR; 65% (113/173) vs 20% (34/174) in the second-line study and 74% (128/172) vs 45% (77/171) in the first-line study] compared with those of chemotherapy (Shaw et al., 2013; Solomon et al., 2014). However, although crizotinib has shown significant treatment efficacy in ALK fusion-positive NSCLC patients, tumor relapse because of acquired resistance has been observed. Crizotinib resistance was shown to be caused by various types of secondary mutations in the ALK kinase domain, by ALK fusion gene amplification, or by activation of the epidermal growth factor receptor (EGFR) or KIT (v-kit hardy-zuckerman 4 feline sarcoma viral oncogene homolog)-mediated bypass pathways (Doebele et al., 2012; Katayama et al., 2012; Sasaki et al., 2011). Crizotinib has also been shown to be relatively ineffective for cancer that has metastasized to the brain because of poor blood–brain barrier (BBB) penetration by P-glycoprotein (P-gp) overexpression (Costa et al., 2011; Chuan Tang et al., 2014). To overcome crizotinib resistance, various next-generation ALK inhibitors have been evaluated in clinical trials. Among these, two ALK-tyrosine kinase inhibitors (TKIs) alectinib and ceritinib, have revealed prominent responses in both ALK-TKI-naïve and crizotinib-treated patients (Sakamoto et al., 2011; Shaw et al., 2014; Gadgeel et al., 2014; Seto et al., 2013; Marsilje et al., 2013). Encouraged by these significant clinical responses (Shaw et al., 2014), ceritinib was approved for clinical use by the US Food and Drug Administration (FDA) in 2014 and European Medicines Agency (EMA) in 2015, and alectinib was approved by the Pharmaceuticals and Medical Devices Agency of Japan in 2014 and FDA in 2015 (Seto et al., 2013). However, it is expected that next-generation ALK inhibitor-resistant tumors will also eventually develop via multiple mechanisms. To date, a few ceritinib-resistant mutations in the ALK kinase domain have been identified in patients who experienced a relapse during ceritinib therapy (Friboulet et al., 2014).