Identification of targetable FGFR gene fusions in diverse cancers

Yi Mi Wu, Fengyun Su, Shanker Kalyana-Sundaram, Nickolay Khazanov, Bushra Ateeq, Xuhong Cao, Robert J. Lonigro, Pankaj Vats, Rui Wang, Su Fang Lin, Ann Joy Cheng, Lakshmi P. Kunju, Javed Siddiqui, Scott A. Tomlins, Peter Wyngaard, Seth Sadis, Sameek Roychowdhury, Maha H. Hussain, Felix Y. Feng, Mark M. ZalupskiMoshe Talpaz, Kenneth J. Pienta, Daniel R. Rhodes, Dan R. Robinson, Arul M. Chinnaiyan

Research output: Contribution to journalArticle

373 Scopus citations

Abstract

Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types. SIGNIFICANCE: High-throughput sequencing technologies facilitate defining the mutational landscape of human cancers, which will lead to more precise treatment of patients with cancer. Here, through integrative sequencing efforts, we identified a variety of FGFR gene fusions in a spectrum of human cancers. FGFR fusions are active kinases. Cells harboring FGFR fusions showed enhanced sensitivity to the FGFR inhibitors PD173074 and pazopanib, suggesting that patients with cancer with FGFR fusions may benefit from targeted FGFR kinase inhibition.

Original languageEnglish (US)
Pages (from-to)636-647
Number of pages12
JournalCancer discovery
Volume3
Issue number6
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Identification of targetable FGFR gene fusions in diverse cancers'. Together they form a unique fingerprint.

  • Cite this

    Wu, Y. M., Su, F., Kalyana-Sundaram, S., Khazanov, N., Ateeq, B., Cao, X., Lonigro, R. J., Vats, P., Wang, R., Lin, S. F., Cheng, A. J., Kunju, L. P., Siddiqui, J., Tomlins, S. A., Wyngaard, P., Sadis, S., Roychowdhury, S., Hussain, M. H., Feng, F. Y., ... Chinnaiyan, A. M. (2013). Identification of targetable FGFR gene fusions in diverse cancers. Cancer discovery, 3(6), 636-647. https://doi.org/10.1158/2159-8290.CD-13-0050