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 Zalupski, Moshe Talpaz, Kenneth J Pienta, Daniel R Rhodes, Dan R Robinson, Arul M Chinnaiyan, 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 Zalupski, Moshe Talpaz, Kenneth J Pienta, Daniel R Rhodes, Dan R Robinson, Arul M Chinnaiyan
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.
Conflict of interest statement
Disclosure of Potential Conflicts Of Interest
A.M.C. is a consultant to Life Technologies, co-founder of Compendia Biosciences, which is now owned by Life Technologies, and advisor to Ventana/Roche and Gen-Probe/Hologic.
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Source: PubMed