Journal Article

Characterization of a KLK2-FGFR2 fusion gene in two cases of metastatic prostate cancer

Barker, Hannah, Clinton, Steven K, Reeser, Julie W, Dao Thuy, Freud, Aharon G, Roychowdhury Sameek, Smith, Amy M, Dorrelyn, Martin, Wing, Michele R, Samorodnitsky, Eric, Paul, Monk J, Hui-Zi, Chen, Bonneville, Russell, Miya Jharna, Krook, Melanie A

2019

Overview

BackgroundThe fibroblast growth factor receptor (FGFR) signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Multiple small molecule kinase inhibitors targeting FGFR are currently being evaluated in clinical trials for patients with FGFR chromosomal translocations. Patients with novel gene fusions involving FGFR may represent candidates for kinase inhibitors.MethodsA targeted RNA-sequencing assay identified a KLK2-FGFR2 fusion gene in two patients with metastatic prostate cancer. NIH3T3 cells were transduced to express the KLK2-FGFR2 fusion. Migration assays, Western blots, and drug sensitivity assays were performed to functionally characterize the fusion.ResultsExpression of the KLK2-FGFR2 fusion protein in NIH3T3 cells induced a profound morphological change promoting enhanced migration and activation of downstream proteins in FGFR signaling pathways. The KLK2-FGFR2 fusion protein was determined to be highly sensitive to the selective FGFR inhibitors AZD-4547, BGJ398, JNJ-42756943, the irreversible inhibitor TAS-120, and the non-selective inhibitor Ponatinib. The KLK2-FGFR2 fusion did not exhibit sensitivity to the non-selective inhibitor Dovitinib.ConclusionsImportantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.

• Publisher: Nature Publishing Group
• Subject: Assaying / Cell fusion / Chromosome translocations / Clinical trials / Fibroblast growth factor receptor 2 / Fibroblast growth factor receptors / Fusion protein / Gene sequencing / Growth factors / Inhibitors / Kinases / Metastases / Metastasis / Prostate cancer / Proteins / Ribonucleic acid / RNA / Sensitivity / Signal transduction / Signaling / Western blotting