Abstract 4759: Identification of ALK, ROS1, FGFR2 and NRG1 Fusions and Validation with Targeted Inhibitors in Lung and Ovarian PDX Models

Chromosomal rearrangement mediated gene fusions and activation of oncogenic signaling pathways have become druggable targets for therapeutic intervention, with successful development of Imatinib as an inhibitor of Bcr-Abl in treatment of Philadelphia chromosome positive chronic myelogenous leukemia. A recent study by Stransky et. al. reported systemic analysis of the transcriptome of nearly 7000 human tumor samples from the Cancer Genome Atlas and revealed the landscape of near twenty kinase fusions across twenty solid tumor types. Identification of corresponding PDX models that carry given kinase fusions would be of paramount interest for preclinical validation of candidate inhibitors. We have established about 1000 PDX models across 20 tumor types. Here we report the identification of ALK, ROS1, FGFR2 fusions in lung cancer PDX models and a NRG1 fusion in the ovarian cancer models by RNA using Sequencing data combined with the Chimerascan and Star-Fusion software for fusion calling.. The gene fusions, as validated by PCR and Sanger Sequencing, led to over-expression of the affected kinases, supporting the notion that kinase activation may be the oncogenic driver in the corresponding tumors. We further validated that ALK inhibitors Crizotinib, AP26113 and LDK378 exhibited robust antitumor activities in the ALK fusion model. Current works on validation of ROS1, FGFR2 and NRG1 inhibitors in the pertinent fusion models are under progression. These models should provide means for pre-clinical validation of novel kinase inhibitors and for experimenting novel combinatorial therapeutic strategies. Citation Format: Xuzhen Tang, Hua Dong, Yibo Gao, Zhixiang Zhang, Xiangnan Qiang, Baoyuan Zhang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Qingyang Gu, Norman Zhang, Jie He, Qunsheng Ji. Identification of ALK, ROS1, FGFR2 and NRG1 fusions and validation with targeted inhibitors in lung and ovarian PDX models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4759.