RT Journal Article
SR Electronic
T1 Druggable Oncogene Fusions in Invasive Mucinous Lung Adenocarcinoma
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 3087
OP 3093
DO 10.1158/1078-0432.CCR-14-0107
VO 20
IS 12
A1 Nakaoku, Takashi
A1 Tsuta, Koji
A1 Ichikawa, Hitoshi
A1 Shiraishi, Kouya
A1 Sakamoto, Hiromi
A1 Enari, Masato
A1 Furuta, Koh
A1 Shimada, Yoko
A1 Ogiwara, Hideaki
A1 Watanabe, Shun-ichi
A1 Nokihara, Hiroshi
A1 Yasuda, Kazuki
A1 Hiramoto, Masaki
A1 Nammo, Takao
A1 Ishigame, Teruhide
A1 Schetter, Aaron J.
A1 Okayama, Hirokazu
A1 Harris, Curtis C.
A1 Kim, Young Hak
A1 Mishima, Michiaki
A1 Yokota, Jun
A1 Yoshida, Teruhiko
A1 Kohno, Takashi
YR 2014
UL http://clincancerres.aacrjournals.org/content/20/12/3087.abstract
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