PT  - JOURNAL ARTICLE
AU  - Nakaoku, Takashi
AU  - Tsuta, Koji
AU  - Ichikawa, Hitoshi
AU  - Shiraishi, Kouya
AU  - Sakamoto, Hiromi
AU  - Enari, Masato
AU  - Furuta, Koh
AU  - Shimada, Yoko
AU  - Ogiwara, Hideaki
AU  - Watanabe, Shun-ichi
AU  - Nokihara, Hiroshi
AU  - Yasuda, Kazuki
AU  - Hiramoto, Masaki
AU  - Nammo, Takao
AU  - Ishigame, Teruhide
AU  - Schetter, Aaron J.
AU  - Okayama, Hirokazu
AU  - Harris, Curtis C.
AU  - Kim, Young Hak
AU  - Mishima, Michiaki
AU  - Yokota, Jun
AU  - Yoshida, Teruhiko
AU  - Kohno, Takashi
TI  - Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma
AID  - 10.1158/1078-0432.CCR-14-0107
DP  - 2014 Jun 15
TA  - Clinical Cancer Research
PG  - 3087--3093
VI  - 20
IP  - 12
4099  - http://clincancerres.aacrjournals.org/content/20/12/3087.short
4100  - http://clincancerres.aacrjournals.org/content/20/12/3087.full
SO  - Clin Cancer Res2014 Jun 15; 20
AB  - Purpose: To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur. Experimental Design: From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products. Results: We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use. Conclusions: Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs. Clin Cancer Res; 20(12); 3087–93. ©2014 AACR.This article is featured in Highlights of This Issue, p. 3045