Identification and Characterization of ALK Kinase Splicing Isoforms in Non–Small-Cell Lung Cancer

摘要: Introduction: Anaplastic lymphoma kinase ( ALK ) rearrangements are present in an important subset of non–small-cell lung cancer (NSCLC) and predict for response to the tyrosine inhibitor crizotinib. In this study, we evaluated yet unknown frequency functional role splicing isoforms NSCLC. Methods: We analyzed 270 cases NSCLC domain aberrations addition generated constructs with full-length echinoderm microtubule-associated protein-like 4 EML4 )- (E13;A20) a isoform. Results: Splicing —including complete skipping exon 23 del23, p.I1171fs*42) 27 del27, p.T1312fs*0)—were identified 11.1% (30 cases) NSCLC, these changes coexisted rearrangements, KRAS mutations, EGFR mutations. were observed EML4-ALK crizotinib-naive treated NSCLCs. T1312fs*0 was unable render cells solely dependent on signaling. Unlike p.L1196M, did not autophosphorylate or other phosphotyrosine sites. Coexpression equal amounts result resistance crizotinib, whereas coexpression L1196M resulted inhibition by Conclusions: even if translated seemed be nonfunctional variants ALK.