KIF5B-RET fusions in lung adenocarcinoma

Abstract

We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.

Figure 1

KIF5B-RET fusions in LADC. (a) Schematic representations of the wild-type KIF5B and RET proteins as well as the four fusion variants identified in this study. The breakpoints for each variant are indicated with red lines. CC, coiled coil; TM, transmembrane. (c) Detection of KIF5B-RET fusions by RT-PCR. RT-PCR products for the RET kinase domain (exons 12 and 13) and GAPDH are shown below. Six LADCs positive for KIF5B-RET fusions (T) are shown, with four corresponding non-cancerous lung tissues (N), a no-template control (NTC) and one LADC that was negative for the fusion (BR0019). (c) Activation of RET kinase activity in the KIF5B-RET protein and the suppression of this activity by vandetanib. H1299 lung cancer cells were transfected with an empty vector, wild-type RET (RET) or KIF5B-RET expression plasmids and treated either with DMSO (serum) or vandetanib, as indicated. The ratios of phosphorylated Tyr905 (pTyr905) RET to total RET signals with respect to wild-type RET after the serum treatment are listed below the gels. (d) Anchorage-independent growth of NIH3T3 cells expressing KIF5B-RET protein and the suppression of this growth by vandetanib. Representative pictures of colonies without vandetanib treatment (top). Scale bars, 50 μm. Bar graph showing the percentage (± s.d.) of colonies formed after treatment with the indicated amounts of vandetanib (average results of three independent experiments) with respect to those formed by DMSO-treated cells. The study was approved by the institutional review boards of institutions participating in this study.