Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma

• DOI: 10.1038/cr.2016.111
• Publication Date: 2016-09-27T11:20:40Z
• Authors: Fei Li; Zhaoyuan Fang; Jian Zhang; Chen Li; Hongyan Liu; Jufeng Xia; Hongwen Zhu; Chenchen Guo; Zhen Qin; Fuming Li; Xiangkun Han; Yuetong Wang; Yan Feng; Ye Wang; Wenjing Zhang; Zuoyun Wang; Yujuan Jin; Yihua Sun; Wenyi Wei; Rong Zeng; Haiquan Chen; Hongbin Ji
• Keywords: Mitogen-Activated Protein Kinase 1; 0301 basic medicine; Lung Neoplasms; Mitogen-Activated Protein Kinase 3; Oncogene Proteins, Fusion; Serine-Arginine Splicing Factors; Intracellular Signaling Peptides and Proteins; Mice, Nude; Nerve Tissue Proteins; Axonemal Dyneins; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Carcinoma, Squamous Cell; Animals; Humans; Sirtuins; Benzimidazoles; Gene Fusion; Matrix Metalloproteinase 1; Cell Proliferation; Signal Transduction

Lung squamous cell carcinoma (SCC) is one of the major subtypes of lung cancer. Our current knowledge of oncogenic drivers in this specific subtype of lung cancer is largely limited compared with lung adenocarcinoma (ADC). Through exon array analyses, molecular analyses and functional studies, we here identify the TRA2B-DNAH5 fusion as a novel oncogenic driver in lung SCC. We found that this gene fusion occurs exclusively in lung SCC (3.1%, 5/163), but not in lung ADC (0/119). Through mechanistic studies, we further revealed that this TRA2B-DNAH5 fusion promotes lung SCC malignant progression through regulating a SIRT6-ERK1/2-MMP1 signaling axis. We show that inhibition of ERK1/2 activation using selumetinib efficiently inhibits the growth of lung SCC with TRA2B-DNAH5 fusion expression. These findings improve our current knowledge of oncogenic drivers in lung SCC and provide a potential therapeutic strategy for lung SCC patients with TRA2B-DNAH5 fusion.