The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)

Abstract

Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways. Key issues to resolve for the optimal implementation of established and emerging treatment modalities for ALK-rearranged NSCLC therapy include the high cost of the targeted inhibitors and the potential of exacerbated toxicities with combination therapies.

Keywords: ALK; Anaplastic lymphoma kinase; Cell signalling; Lung cancer; Molecular-targeted therapy.

Fig. 1

EML4-ALK fusion and its signaling network. a Diagram shows the fusion of the N-terminal portion of EML4, which contains its basic region, the echinoderm microtubule-associated protein-like protein (HELP) domain, and part of the WD-repeat region, to the intracellular region of ALK, containing the tyrosine kinase domain. The transmembrane (TM) domain is not present in the final fusion product. Reproduced from ref. [25]. b EML4-ALK protein complex network (interactome) constructed using a tandem affinity purification approach followed by mass spectrometry. Reproduced from ref. [39]

Fig. 2

Diagnostic methods for the detection of ALK rearrangement and expression in NSCLC. a FISH: arrows in the upper picture exemplify the split signal pattern, while the ones in the bottom picture specified the single red signal pattern. b IHC using the D5F3 ALK assay. c Diagrammatic representation of full length ALK and the EML4-ALK fusion transcripts indicating ALK domains in the ALK protein, location of ALK RT-PCR primers (black arrows) and the fluorescent probe (green bar) used in the ALK RGQ RT-PCR Kit (Qiagen). TM: transmembrane. d Comparison of two commercially available methods to generate libraries for NGS. a and b adapted from ref. [45]. c reproduced from ref. [42]. d reproduced from ref. [46]

Fig. 3

Timeline of ALK Inhibitor Development in NSCLC. EML4-ALK discovery in NSCLC cancer led to the development of first-generation inhibitor crizotinib in 2007. Phase III clinical trials in 2013 and 2014 demonstrated that crizotinib was effective as first line therapy. Due to drug resistance to crizotinib, second-generation inhibitors ceritinib, alectinib and brigatinib were developed. Third-generation inhibitor loratinib is currently in phase III clinical trials. Figure was based on information in references [30, 34, 47, 48, 64, 65, 83]. Chemical structures for the following ALK TKI: crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib were obtained from PubChem [–104]

Fig. 4

Examples of known mutations in the tyrosine kinase domain of ALK and their influence on kinase activity and drug response. Schematic diagram of the tyrosine kinase domain of the ALK receptor with the location of known mutations. The mechanisms discussed in this review that promote kinase activity and resistance, if known, are indicated. Figure was based on information in references [–58, 71, 72, 83]