Invasive mucinous adenocarcinoma (IMA) of lung, a subtype of lung adenocarcinoma, is known to be strongly associated with KRAS mutation. Genetic aberration is unknown in IMA without KRAS mutation.

From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations, we conducted whole-transcriptome sequencing on 32 IMAs, including 27 cases without KRAS mutation. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1 (NRG1 fusions: 6/90), EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET.

The CD74-NRG1 and SLC3A2-NRG1 fusion proteins contained the transmembrane domain of CD74 and SLC3A2 and retained the EGF-like domain of the NRG1 protein (NRG1 III-β3 form). Membrane-tethered EGF-like domain might activate juxtacrine signaling through HER2:HER3 receptors. To reveal the mechanism of the oncogenicity, exposing EFM-19 cells which express HER2 and HER3 to conditioned media from H1299 cells expressing exogenous CD74-NRG1 fusion protein resulted in phosphorylation of HER2 and HER3, and downstream mitogen-activated kinase and AKT. The phosphorylation was suppressed by lapatinib and afatinib.

When EZR-ERBB4 or TRIM24-BRAF cDNA was exogenously expressed in NIH3T3 cells, ERBB4 or downstream mediator of BRAF was phosphorylated under serum-free condition. The expression of fusion genes induced anchorage-independent growth. The phosphorylation and growth were suppressed by the kinase inhibitors targeting fusion-induced signaling.

These results show that the NRG1, ERBB4 and BRAF fusions are novel driver mutations and potential targets. About 15% (13/90; 14.4%) of IMAs harbor druggable aberrations, taken together a small fraction of known driver aberrations.

Citation Format: Takashi Nakaoku, Koji Tsuta, Hitoshi Ichikawa, Kouya Shiraishi, Hiromi Sakamoto, Masato Enari, Koh Furuta, Yoko Shimada, Hideaki Ogiwara, Shun-ichi Watanabe, Hiroshi Nokihara, Kazuki Yasuda, Masaki Hiramoto, Takao Nammo, Young Hak Kim, Michiaki Mishima, Jun Yokota, Teruhiko Yoshida, Takashi Kohno. Druggable oncogene fusions in lung invasive mucinous adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4669. doi:10.1158/1538-7445.AM2015-4669