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Clinical Research

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

Prostate Cancer and Prostatic Diseases volume 22, pages 624–632 (2019)Cite this article

Subjects

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.

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Acknowledgements

The authors thank current and past members of the Roychowdhury laboratory for their insight and discussion regarding these studies. The authors would like to also thank Jenny Badillo for administrative support for the research team. S.R. has received support from an American Cancer Society grant MRSG-12-194-01-TBG, the Prostate Cancer Foundation, NCI UH2CA202971 (SpARKFuse), NCI UH2CA216432 (MSIDx), American Lung Association, and Pelotonia. M.A.K. was supported by a T32 Oncology Training Grant (5T32CA009338) and Award Number Grant TL1TR002735 from the National Center for Advancing Translational Sciences. R.B. was in part supported by a T32 T32GM068412 and a Pelotonia graduate student fellowship. H.Z.C. was supported by a Pelotonia post-doctoral fellowship and an ASCO Conquer Cancer Foundation Young Investigator Award. M.R.W. was supported by the Helene Fuld Health Trust Nursing Scholarship.

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Authors and Affiliations

  1. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

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

  2. Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA

    Aharon G. Freud

  3. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA

    J. Paul Monk, Steven K. Clinton & Sameek Roychowdhury

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Correspondence to Sameek Roychowdhury.

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Conflict of interest

SR participated in Advisory Boards for Incyte Corporation (2017), AbbVie, Inc. (2017), and QED Therapeutics (2018). SR received honoraria from IDT Integrated DNA Technologies (2017), Illumina (2018). The remaining authors declare that they have no conflict of interest.

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Krook, M.A., Barker, H., Chen, HZ. et al. Characterization of a KLK2-FGFR2 fusion gene in two cases of metastatic prostate cancer. Prostate Cancer Prostatic Dis 22, 624–632 (2019). https://doi.org/10.1038/s41391-019-0145-2

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