Rearrangements of the proto-oncogene RET are newly identified potential driver mutations in lung adenocarcinoma (LAD). However, the absence of cell lines harboring RET fusion genes has hampered the investigation of the biological relevance of RET and the development of RET-targeted therapy. Thus, we aimed to identify a RET fusion positive LAD cell line. Eleven LAD cell lines were screened for RET fusion transcripts by reverse transcription-polymerase chain reaction. The biological relevance of the CCDC6-RET gene products was assessed by cell growth, survival and phosphorylation of ERK1 ⁄ 2 and AKT with or without the suppression of RET expression using RNA interference. The efficacy of RET inhibitors was evaluated in vitro using a culture system and in an in vivo xenograft model. Expression of the CCDC6-RET fusion gene in LC-2 ⁄ ad cells was demonstrated by the mRNA and protein levels, and the genomic break-point was confirmed by genomic DNA sequencing. Mutations in KRAS and EGFR were not observed in the LC-2 ⁄ ad cells. CCDC6-RET was constitutively active, and the introduction of a siRNA targeting the RET 3' region decreased cell proliferation by downregulating RET and ERK1 ⁄ 2 phosphorylation. Moreover, treatment with RETinhibitors, including vandetanib, reduced cell viability, which was accompanied by the downregulation of the AKT and ERK1 ⁄ 2 signaling pathways. Vandetanib exhibited anti-tumor effects in the xenograft model. Endogenously expressing CCDC6-RET contributed to cell growth. The inhibition of kinase activity could be an effective treatment strategy for LAD. LC-2 ⁄ ad is a useful model for developing fusion RET-targeted therapy. (Cancer Sci 2013; 104: 896-903) L ung cancer is the most common cause of cancer death worldwide.(1) The identification of oncogenic driver genes is to select the increasing number of small molecule inhibitors targeting these gene products. (2,3) In particular, in lung adenocarcinoma (LAD), the most dominant histological subtype of lung cancer, the application of kinase inhibitors for cases with specific gene alterations has been successful, that is, gefitinib and erlotinib for EGFR mutation-positive cases and crizotinib for ALK fusion-positive cases.(4-7) Furthermore, accumulating evidence has demonstrated somatic mutations and rearrangements of potential oncogenes, including BRAF, ERBB2 and ROS1, in LAD. (8)(9)(10) RET is one of the newest LAD driver genes. (11)(12)(13)(14)(15) RET gene is located on chromosome 10 and encodes a receptor tyrosine kinase, (16,17) and the oncogenic potential of this gene product has been suggested in several tumors, including thyroid cancer. (18)(19)(20) Recently, five independent groups identified aberrant fusion genes, KIF5B-RET and CCDC6-RET in clinical samples of LAD.(11-15) Ectopically expressed RET fusion products afforded NIH3T3 cells with anchorage-independent growth and tumorigenicity in nude mice. (11,14) Furthermore, KIF5B-RET-expressing H1299 cells exhibited growth factorindependent growth.(11) These findings strongly suggest ...