The discovery of the novel KIF5B-ALK variant further consolidated the role of aberrant ALK signaling in lung carcinogenesis.

BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is frequently involved in chromosomal translocations resulting in fusion genes with different partners found in various lympho-proliferative conditions. In non-small cell lung cancers (NSCLC), the fusion protein encoded by echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene was recently reported to confer oncogenic properties. This study aimed to identify other possible ALK fusion genes and analyze their oncogenic potentials. METHODS: Immunohistochemical analysis was used to screen for aberrant ALK expression in primary NSCLC. 5’ rapid amplification of cDNA ends was used to screen for potential novel 5’ fusion partners of ALK other than EML4-ALK. Reverse transcription polymerase chain reaction and fluorescence in situ hybridization were used to confirm the identity of 5’fusion partner. The genomic breakpoint was verified using genomic sequencing. Overexpression of the novel ALK fusion gene and variants 3a and 3b of EML4-ALK was performed to assess downstream signaling and functional effects. RESULTS: We identified a novel gene resulting from fusion of kinesin family member 5B (KIF5B) exon 15 to ALK exon 20 in a primary lung adenocarcinoma. Western blot of the clinical tumor tissues showed expression of a protein whose size correlated with that of the predicted KIF5B-ALK. Overexpression of KIF5B-ALK in mammalian cells led to STAT3 and AKT activation, enhanced cell proliferation, migration and invasion. These oncogenic properties were comparable to those of EML4-ALK variants. CONCLUSIONS: The discovery of the novel KIF5B-ALK variant with transforming functions further consolidates the role of aberrant ALK signaling in lung carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1121. doi:10.1158/1538-7445.AM2011-1121