In 2007, rearrangements of the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) were reported (Soda et al., 2007). Less than 3 years later, studies of ALK inhibition yielding dramatic response rates in patients with advanced NSCLC containing ALK-rearrangements and determination of the mechanism of resistance to the ALK-targeted therapy were reported in the New England Journal of Medicine (Choi et al., 2010; Kwak et al., 2010). Together, these reports represent a stunning and rapid translation of preclinical molecular findings into the clinic. In a pretreated patient population that generally has a 10% response rate to conventional chemotherapy, treatment with the oral ALK inhibitor crizotinib yielded an overall response rate of 55% and an estimated 6 month, progression-free survival rate of 72%. In addition, the mechanism of resistance was associated with mutations in the ALK kinase domain, providing genetic evidence that ALK was indeed the target of the “targeted” therapy. During this brief period, translational research provided insights into ALK biology, clinicopathologic features of the target population, development of a clinical diagnostic test, drug development, and identification of resistance mechanisms. By contrast, analogous development for other druggable kinases, such as breakpoint cluster region-Abelson (BCR-ABL) in chronic myeloid leukemia and epidermal growth factor receptor (EGFR) mutations in NSCLC, unfolded over decades (see Table 1). This rapid clinical development of ALK-targeted therapy was greatly accelerated, in part by previous experience with clinical development of other tyrosine kinase inhibitors (TKIs) and in part by the fact that crizotinib (PF-02341066, Pfizer), which was developed initially as a MET inhibitor but was soon realized to also be an ALK inhibitor, was developed before the EML4-ALK translocation was identified in NSCLC (Christensen et al., 2007; Zou et al., 2007).

ALK encodes a tyrosine kinase normally expressed only in certain neuronal cells. The ALK gene was originally identified through cloning of the t(2;5)(p23;q35) translocation found in a subset of anaplastic large cell lymphomas (Morris et al., 1994). In a rare subset of NSCLCs, interstitial deletion and inversion within chromosome 2p result in fusion of the N-terminal portion of the protein encoded by the echinoderm microtubule-associated protein-like 4 (EML4) gene with the intracellular signaling portion of the ALK receptor tyrosine kinase (Soda et al., 2007). While genetic alterations involving ALK have been identified in other malignancies, thus far, the EML4-ALK fusion gene appears unique to NSCLC. A number of EML4-ALK variants have been identified in NSCLCs, all of which appear to confer gain-of-function properties (Choi et al., 2008). Equivalent to EGFR mutations, EML4-ALK fusions result in constitutive tyrosine kinase activity, dependence of the cancer cell on activated downstream mitogenic pathways, and exquisite sensitivity to ALK inhibition, and thus represents another case of “oncogene addiction” (Weinstein and Joe, 2008).

Identification of the precise mechanism(s) by which tumors become resistant to targeted therapy has yielded important information and thus needs to be studied in initial clinical trials, acknowledging that such study requires rebiopsying of patient’s tumors at the time of relapse. Thus, it was of great interest that accompanying the report of the crizotinib clinical trial, molecular analysis of an EML4-ALK fusion NSCLC that had relapsed on crizotinib therapy was reported by another group (Choi et al., 2010). The resistant tumor had acquired two mutations in the tumor ALK tyrosine kinase domain (C1156Y and L1196M) that appear to be in two subpopulations of tumor cells. In vitro, cells engineered to express either of these mutant ALK fusion proteins were resistant to crizotinib and other ALK inhibitors compared to ALK fusion protein without these changes. The authors presented pictures of the predicted ALK structure, locating the mutations with reference to the crizotinib binding site, and noted that amino acid L1196M corresponds to the imatinib resistance BCR-ABL T315I mutation found in chronic myelogenous leukemias, and gefitinib and erlotinib resistance EGFR T790M mutation found in NSCLCs. These findings strongly suggest L1196M is a “gatekeeper” mutation, which confers resistance to tyrosine kinase inhibitors via altered ATP binding and steric hindrance of drug binding. The mechanism of resistance of C1156, an activating mutation on the N-terminal side of ALK, is less clear.