Identification of a novel ALK variant intrinsically resistant to crizotinib

The knowledge of oncogene addiction in non small cell lung carcinoma (NSCLC) involving EGFR, ALK and ROS1 genes has changed the therapeutic and prognostic landscape of NSCLC. ALK rearranged NSCLC accounts for 10% of these cases, and with the development and approval of ALK TKIs (tyrosine kinase inhibitors) like crizotinib, it is imperative to detect the same. Various ALK variants are known to occur resulting in differential sensitivities to TKIs because of different protein stabilities. The precise characterization hence is important which can be achieved only by high throughput next generation sequencing (NGS) based assays. Immunohistochemistry and FISH (fluorescence in situ hybridization) although considered gold standards cannot define the breakpoints and length of the fusion transcripts. We herein report a novel EML4 -ALK variant in a case of advanced NSCLC which plausibly is inherently resistant to crizotinib because of the breakpoints involved.