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Oncotarget. 2016 Jun 14;7(24):36101-36114. doi: 10.18632/oncotarget.9137.

Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma.

Lee MS1,2, Kim RN3,4, I H5,6, Oh DY1,2, Song JY2, Noh KW1,2, Kim YJ1,2, Yang JW7, Lira ME8, Lee CH9, Lee MK10, Kim YD5, Mao M8,11, Han J12, Kim J13, Choi YL1,2,12.

Author information

1
Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.
2
Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
3
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
4
Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea.
5
Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine, Busan, Korea.
6
Pusan National University Hospital Biomedical Research Institute, Busan, Korea.
7
Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea.
8
Pfizer Oncology, San Diego, California, USA.
9
Department of Pathology, Pusan National University School of Medicine, Busan, Korea.
10
Department of Pulmonology Allergy and Critical Care Medicine, Pusan National University School of Medicine, Busan, Korea.
11
Present address: BGI Genomics, Shenzhen, China.
12
Departments of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.
13
Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea.

Abstract

REarranged during Transfection (RET) fusion genes are detected in approximately 1% of lung adenocarcinomas and known primarily as oncogenic driver factors. Here, we found a novel RET fusion gene, KIAA1217-RET, and examined the functional differences of RET51 and RET9 protein, fused with KIAA1217 in cancer progression and drug response. KIAA1217-RET, resulting from the rearrangement of chromosome 10, was generated by the fusion of KIAA1217 exon 11 and RET exon 11 from a non-small cell lung cancer patient. Expression of this gene led to increased cell growth and invasive properties through activations of the PI3K/AKT and ERK signaling pathways and subsequently enabled oncogenic transformation of lung cells. We observed that cells expressing KIAA1217-RET9 fusion protein were more sensitive to vandetanib than those expressing KIAA1217-RET51 and both isoforms attenuated cellular growth via cell cycle arrest. These results demonstrated that KIAA1217-RET fusion represents a novel oncogenic driver gene, the products of which are sensitive to vandetanib treatment, and suggested that the KIAA1217-RET-fusion gene is a promising target for lung cancer treatment.

KEYWORDS:

KIAA1217; KIAA1217-RET fusion; RET; lung cancer; oncogenic driver

PMID:
27150058
PMCID:
PMC5094986
DOI:
10.18632/oncotarget.9137
[Indexed for MEDLINE]
Free PMC Article

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