Faculty Collaboration Database

Characterization of a KLK2-FGFR2 fusion gene in two cases of metastatic prostate cancer. Prostate Cancer Prostatic Dis 2019 Dec;22(4):624-632

Date

05/03/2019

Pubmed ID

31043681

Pubmed Central ID

PMC6824932

DOI

10.1038/s41391-019-0145-2

Scopus ID

2-s2.0-85065245470 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

BACKGROUND: The 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.

METHODS: A 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.

RESULTS: Expression 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.

CONCLUSIONS: Importantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.

Author List

Krook MA, Barker H, Chen HZ, Reeser JW, Wing MR, Martin D, Smith AM, Dao T, Bonneville R, Samorodnitsky E, Miya J, Freud AG, Monk JP, Clinton SK, Roychowdhury S

Author

Hui-Zi Chen MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinogenesis
Cell Movement
HEK293 Cells
Humans
Kallikreins
Male
Mice
Middle Aged
Molecular Targeted Therapy
NIH 3T3 Cells
Oncogene Proteins, Fusion
Precision Medicine
Prostatic Neoplasms
Protein Kinase Inhibitors
Receptor, Fibroblast Growth Factor, Type 2
Recombinant Fusion Proteins
Sequence Analysis, RNA
Transfection