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Disclosure
Acknowledgments
Introduction Deeper understanding of the pathobiology of non-small cell lung cancer (NSCLC) has led to the development of small 3ma that target genetic mutations known to play critical roles in the progression to metastatic disease. Mutations in epidermal growth factor receptor (EGFR), kirsten ras sarcoma oncogene (KRAS) and anaplastic lymphoma kinase (ALK) translocations are generally mutually exclusive in patients with NSCLC and the presence of one alteration in lieu of another can influence responses to targeted therapy. Thus, testing for these mutations and tailoring therapy accordingly is widely accepted as standard practice (National Comprehensive Cancer Network, 2015; Keedy et al., 2011; Stella et al., 2013). ALK gene rearrangement in NSCLC was identified for the first time in a resected adenocarcinoma specimen from a 62-year-old male smoker. Rearrangements, either inversions or translocations, characterize the genomic disruptions involving ALK observed in NSCLC (Soda et al., 2007a; Ou et al., 2012). Inversions in the short arm of chromosome 2 that juxtapose echinoderm microtubule–associated protein-like 4 (EML4) with ALK and produce EML4-ALK–fusion tyrosine kinases (Soda et al., 2007a; Choi et al., 2008) are the most common noted changes but at least 27 fusion variants have been identified (Sasaki et al., 2010). The reported prevalence of ALK rearrangements in unselected NSCLC is approximately 5% (Inamura et al., 2008; Rodig et al., 2009). Remarkably, tumors with ALK rearrangements are addicted to ALK signalling and are inhibited by ALK Tyrosine Kinase Inhibitors (TKIs) in preclinical models (Christensen et al., 2007; Settleman, 2009; McDermott et al., 2008). In the past years several ALK inhibitors (ALKi) have been developed and become widely available in clinical practice; they are listed in Table 1 with indication/approval along with the registration trials. Despite the efficacy of all these drugs, all ALK+ lung cancer patients will inevitably progress at some point during their treatment. To date, we are aware of two major mechanisms of resistance: ALK-dependent (primary resistance, secondary acquired mutations, gene amplification) and ALK-independent (by-pass signalling, drug efflux pump, epithelial-to-mesenchymal transition). Mechanisms of primary resistance are poorly understood and the spectrum of known secondary mutations mirrors Chronic Myeloid Leukemia (CML) and its mutational landscape acquired during imatinib treatment (Von Bubnoff et al., 2002). The most common and well established mechanism of resistance for the EGFR is the alteration of the driver oncogene, where the gatekeeper T790M mutation is found in ∼50% of EGFR-mutant patients who become resistant to EGFR inhibition (Pao et al., 2005; Ma et al., 2011). This has led to the development of several third-generation EGFR inhibitors, that could potentially block the growth of EGFR T790M-positive tumors (Cross et al., 2014; Walter et al., 2013; Park et al., 2015a). Unlike EGFR, type and frequency of ALK resistant mutations changes based on the inhibitor class. In crizotinib-refractory patients the most frequent mutations are L1196M and G1269A. The first is a classical gatekeeper mutation that alters the catalytic domain and causes resistance to ATP-competitive inhibitors (Choi et al., 2010), as in EGFR-T790M+ lung cancers. The latter, G1269A, determines a steric hindrance impairing the proper binding of crizotinib (Doebele et al., 2012). A plethora of less frequent mutations have been also described such as C1156Y, L1152R, 1151 T-ins at the N-terminus domain, I1171T, F1174L near the activation loop and G1202R, S1206Y in the solvent-exposed region close by the crizotinib binding-site (Sasaki et al., 2011; Katayama et al., 2017; Toyokawa et al., 2014; Katayama et al., 2011). Patients progressing on crizotinib treatment, regardless the presence of acquired mutations or not, seemed to be still ALK-dependent, as they respond to next-generation inhibitors, probably due to the limited ALK-blockade potency of crizotinib (Ignatius Ou et al., 2014).