Abstract 497: Understanding oncogenic fusions: Lessons learned from inflammatory myofibroblastic tumor

Abstract

Abstract Oncogenic kinase fusions are validated targets for cancer therapy. With the advent of next generation sequencing (NGS) based clinical diagnostic tools, the detection of these kinase fusions is rapidly increasing across multiple adult and pediatric tumor types. However, there remains a need to better understand the functional impact of these fusions in order to help direct clinical therapies. To study fusion biology, we have made use of a large collection of inflammatory myofibroblastic tumor (IMT) samples. IMT is a rare mesenchymal malignancy, which typically occurs in children. We have recently demonstrated that IMTs harbor multiple therapeutically actionable kinase fusions, including ALK, ROS1, and PDGFRB fusions, using a targeted capture-based NGS assay in a CLIA laboratory (Foundation Medicine). Our initial results demonstrated both previously described ALK fusions, including TPM3-, TPM4-, TFG-, and RANBP2-ALK as well as novel ALK fusions, including PRKAR1A-ALK and LMNA-ALK. Although the presence of ALK fusions within a tumor has been correlated with response to ALK inhibitor therapy, the role that the 5′ prime partner gene may play in the functional biology of the fusion has not been systematically investigated. To address this, we stably transfected cDNAs encoding LMNA-ALK, RANBP2-ALK, FN1-ALK, TFG-ALK, and PRKAR1A-ALK into BA/F3 cells. All X-ALK (X = the fusion partner) variants were tyrosine phosphorylated and their subcellular distribution was in agreement with that observed in the primary tumors harboring the identical fusion. Subcellular localization was altered as a function of the fusion partner. For example, LMNA-ALK was predominantly cytoplasmic while RANBP2-ALK was predominantly perinuclear. Additionally, we compared proliferation rates, downstream signaling, and sensitivity to various structurally different ALK inhibitors amongst all of the X-ALK fusions. Overall, our results suggest that the specific fusion partner may affect the properties of the ALK fusion protein, including sensitivity to ALK inhibitors currently in clinical use. To date, most ALK fusions are detected by immunohistochemistry for ALK overexpression or by “break-apart” fluorescence in situ hybridization (FISH), techniques which may be falsely negative in some settings and in others cannot discern specific fusion present. As the role of NGS increases in clinical diagnostics, our findings may provide further biological and clinical insights into these kinase fusions. Citation Format: Merrida A. Childress, Abha Gupta, Doron Lipson, Geoff Otto, Tina Brennan, Catherine T. Chung, Scott C. Borinstein, Jeffrey S. Ross, Phillip J. Stephens, Vincent A. Miller, Cheryl M. Coffin, Jason L. Hornick, Christine M. Lovly. Understanding oncogenic fusions: Lessons learned from inflammatory myofibroblastic tumor. [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 497. doi:10.1158/1538-7445.AM2015-497