TY - JOUR
T1 - Identification of targetable FGFR gene fusions in diverse cancers
AU - Wu, Yi Mi
AU - Su, Fengyun
AU - Kalyana-Sundaram, Shanker
AU - Khazanov, Nickolay
AU - Ateeq, Bushra
AU - Cao, Xuhong
AU - Lonigro, Robert J.
AU - Vats, Pankaj
AU - Wang, Rui
AU - Lin, Su Fang
AU - Cheng, Ann Joy
AU - Kunju, Lakshmi P.
AU - Siddiqui, Javed
AU - Tomlins, Scott A.
AU - Wyngaard, Peter
AU - Sadis, Seth
AU - Roychowdhury, Sameek
AU - Hussain, Maha H.
AU - Feng, Felix Y.
AU - Zalupski, Mark M.
AU - Talpaz, Moshe
AU - Pienta, Kenneth J.
AU - Rhodes, Daniel R.
AU - Robinson, Dan R.
AU - Chinnaiyan, Arul M.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84878781242&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-13-0050
DO - 10.1158/2159-8290.CD-13-0050
M3 - 文章
C2 - 23558953
AN - SCOPUS:84878781242
SN - 2159-8274
VL - 3
SP - 636
EP - 647
JO - Cancer Discovery
JF - Cancer Discovery
IS - 6
ER -