Abstract

We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.

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Acknowledgements

This work was supported by the Colorado Bioscience Discovery Evaluation Grant Program, the National Institutes of Health (NIH) NCATS Colorado Clinical and Translational Sciences Institute Grant UL1 TR000154 (contents are the authors' sole responsibility and do not necessarily represent official NIH views) and the Boettcher Foundation's Webb-Waring Biomedical Research Program (R.C.D.), as well as the Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Programs of Research Excellence (SPORE) P50 CA090578 (P.A.J.), the Cammarata Family Foundation Research Fund (M.C. and P.A.J.), the Nirenberg Fellowship at the Dana-Farber Cancer Institute (M.C. and P.A.J.) and the University of Colorado Lung Cancer SPORE grant P50CA058187 and the US National Cancer Institute Cancer Center Support Grant P30CA46934 (M.V.-G.). Ba/F3 cells were a gift from D. Theodorescu (University of Colorado, Anschutz Medical Campus). The cell lines KM12, HCT116, HCT15, HT29 and SW837 were gifts from S.G. Eckhardt (University of Colorado, Anschutz Medical Campus). The cell lines H3122, H1650, H1299 and HCC78 were gifts from J.D. Minna (University of Texas Southwestern). Aythymic nude mice were a gift from J. DeGregori (University of Colorado, Anschutz Medical Campus).

Author information

Author notes

    • Aria Vaishnavi
    •  & Marzia Capelletti

    These authors contributed equally to this work.

    • Pasi A Jänne
    •  & Robert C Doebele

    These authors jointly directed this work.

Affiliations

  1. Department of Medicine, Division of Medical Oncology, University of Colorado School of Medicine, Aurora, Colorado, USA.

    • Aria Vaishnavi
    • , Anh T Le
    • , Kurtis D Davies
    • , Amanda B Pilling
    • , Eamon M Berge
    • , Marileila Varella-Garcia
    •  & Robert C Doebele
  2. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Marzia Capelletti
    • , Mohit Butaney
    • , Dalia Ercan
    • , Peter S Hammerman
    •  & Pasi A Jänne
  3. University of Colorado Cancer Center, Aurora, Colorado, USA.

    • Severine Kako
    • , Sakshi Mahale
    • , Dara L Aisner
    • , Marileila Varella-Garcia
    •  & Robert C Doebele
  4. Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA.

    • Dara L Aisner
  5. Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

    • Jhingook Kim
  6. Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

    • Hidefumi Sasaki
  7. Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

    • Seung-il Park
  8. Broad Institute, Cambridge, Massachusetts, USA.

    • Gregory Kryukov
    •  & Levi A Garraway
  9. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Levi A Garraway
  10. Array BioPharma, Boulder, Colorado, USA.

    • Julia Haas
    •  & Steven W Andrews
  11. Foundation Medicine, Boston, Massachusetts, USA.

    • Doron Lipson
    • , Philip J Stephens
    •  & Vince A Miller
  12. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Pasi A Jänne

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Contributions

R.C.D., P.A.J. and V.A.M. conceived of the research idea. R.C.D. and P.A.J. designed experiments, took responsibility for the oversight of the project and wrote the manuscript. A.V. and D.E. designed and performed immunoblotting, generated Ba/F3 and NIH3T3 cells expressing exogenous NTRK1 fusion constructs, performed flow cytometry and MTS assays and contributed to writing of the manuscript. D.L. and P.J.S. designed and performed NGS assays. M.V.-G. designed FISH probes and interpreted FISH experiments. S.K. and S.M. performed and analyzed FISH experiments. A.T.L. and M.C. performed cloning of RT-PCR fusion constructs. D.L.A. analyzed tumor samples and performed immunohistochemistry. K.D.D. performed in vitro analyses and contributed to interpretation of the data. A.B.P. performed in vivo experiments and contributed to interpretation of data. P.S.H., L.A.G. and G.K. performed bioinformatics analyses. J.H. and S.W.A. designed and profiled ARRY-470. E.M.B. and M.B. collected clinical data. J.K., H.S. and S.P. provided subject specimens. All authors contributed to revision of the manuscript.

Competing interests

R.C.D., M.V.-G. and A.T.L. are listed on a regularized patent application filed with the U.S. Patent and Trademark Office related to NTRK1 as a predictive biomarker in cancer.

Corresponding authors

Correspondence to Pasi A Jänne or Robert C Doebele.

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DOI

https://doi.org/10.1038/nm.3352

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