In large biopsies series from ALK NSCLC treated

In large biopsies series from ALK+ NSCLC treated patients, the number of detected mutations increased after second generation ALKi (Gainor et al., 2016) and in one study were present in 56% of the entire cohort (Shaw et al., 2013b). For example, the rate of G1202R mutations increases from 2% in post-crizotinib treated patients to 43% in post-brigatinib cases highlighting a specific mutational profile associated to each ALK TKI. The C1156Y mutation is less efficiently inhibited by ceritinib, contrary to the I1171T (Shaw et al., 2013a) mutation, identified in post-alectinib samples, that results sensitive to ceritinib. The gatekeeper mutation L1196M is inhibited by alectinib but emerges as a post-alectinib mutation itself; F1174L mutations determine resistance to ceritinib but are still sensitive to alectinib; the G1202R, most common mechanism of resistance post-second-generation ALKi (ceritinib, alectinib, brigatinib), is efficiently inhibited only by the third generation compound, lorlatinib, in preclinical models and patients (Shaw et al., 2013b). This scenario becomes even more complex if we add the presence of compound-related resistance mutations that emerge in patients treated with sequential ALK inhibitors: tumour clones harbouring E1210K/D1203N mutations after crizotinib and brigatinib remains sensitive only to lorlatinib (Shaw et al., 2013b); on the other hand, a double mutant patient (C1156Y/L1198F) resistant to crizotinib, ceritinib and lorlatinib appeared to regain sensitivity to crizotinib, with a durable response (Shaw et al., 2016). If ALK gene amplification has been identified as resistance mechanism only in a small fraction (9%) of crizotinib refractory cases, multiple by-pass signalling tracks, which account for ≈40% of non-mutated patients refractory to second-generation ALKi (Tabbo et al., 2016), have been described: EGFR and HER family members activation (Choi et al., 2017), also triggered by paracrine stimuli (Yamada et al., 2012), MET amplification, activation of downstream signalling pathway (i.e. RAS-MEK), even by specific MAP2K1 mutation that makes cancer DPQ sensitive to ALK/MEK co-inhibition (Crystal et al., 2014), c-KIT amplification requiring SCF, IGF-1R upregulation (Lovly et al., 2014) SRC activation (Shaw et al., 2017b) and engagement of P2Y receptors (Wilson et al., 2015). Notably, efflux (MDR1 encoded) pump over-expression may be considered an alternative mechanism of resistance, as demonstrated in patients treated with crizotinib and ceritinib (Katayama et al., 2015), whose CNS penetration is hindered compared to alectinib that is not a substrate of this drug efflux system. Lastly, transition to a mesenchymal phenotype represents an alternative escape strategy. EMT has been described in post-ceritinib samples (Shaw et al., 2013b) although the real contribution and underlying molecular mechanisms have not been elucidated yet. Some hypothesis came from the similar scenario of EMT in EGFR-mutant NSCLC in which alternative activation of AXL, IGF-1R or the SRC/FAK pathways have been proposed as causative molecular events (Zhang et al., 2012; Zhou et al., 2015; Wilson et al., 2014).
Conclusions
Conflict if interest
Introduction The oncogenic driving character of the tyrosine kinase - anaplastic lymphoma kinase (ALK) fusing with the partner - echinoderm microtubule-associated protein-like 4 (EML4) has been confirmed by the FDA's approval of the first-generation ALK inhibitor crizotinib (1) for treatment of ALK-positive non-small cell lung carcinoma (NSCLC) in the US and some other countries [1,2]. In order to resolve the clinically relevant drug resistance caused by mutations of ALK kinase, second-generation and third-generation ALK inhibitors have been successively approved for clinic use (Fig. 1). Alectinib (2) [3,4], ceritinib (3) [5] and brigatinib (4) [6,7] belong to the second-generation ALK inhibitors with capacity to counteract the resistance of crizotinib. Lorlatinib (5) is the newly approved ALK inhibitor with effectiveness against most of the resistant mutants caused by both the first- and second-generation ALK inhibitors [8]. Despite this progress, however drug resistance of the new inhibitors is unavoidable due to ALK fusion gene amplification, occurrence of new ALK resistant mutations, activation of bypass signaling pathways (EGFR, c-Kit), and many others mechanisms [[9], [10], [11], [12], [13]].