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Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer

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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Figure 1: Discovery and validation of oncogenic NTRK1 gene fusions in lung cancer samples.
Figure 2: Drug treatment inhibits activation of TRKA, downstream signaling and proliferation in cells expressing NTRK1 fusions.

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References

  1. Mok, T.S. et al. N. Engl. J. Med. 361, 947–957 (2009).

    Article  CAS  Google Scholar 

  2. Shaw, A.T. et al. N. Engl. J. Med. 368, 2385–2394 (2013).

    Article  CAS  Google Scholar 

  3. Davies, K.D. et al. Clin. Cancer Res. 18, 4570–4579 (2012).

    Article  CAS  Google Scholar 

  4. Takeuchi, K. et al. Nat. Med. 18, 378–381 (2012).

    Article  CAS  Google Scholar 

  5. Ju, Y.S. et al. Genome Res. 22, 436–445 (2012).

    Article  CAS  Google Scholar 

  6. Kohno, T. et al. Nat. Med. 18, 375–377 (2012).

    Article  CAS  Google Scholar 

  7. Drilon, A. et al. Cancer Discov. 3, 630–635 (2013).

    Article  CAS  Google Scholar 

  8. Majewski, I.J. et al. J. Pathol. 230, 270–276 (2013).

    Article  CAS  Google Scholar 

  9. Wu, Y.M. et al. Cancer Discov. 3, 636–647 (2013).

    Article  CAS  Google Scholar 

  10. Lipson, D. et al. Nat. Med. 18, 382–384 (2012).

    Article  CAS  Google Scholar 

  11. Alberti, L., Carniti, C., Miranda, C., Roccato, E. & Pierotti, M.A. J. Cell Physiol. 195, 168–186 (2003).

    Article  CAS  Google Scholar 

  12. Davies, K.D. & Doebele, R.C. Clin. Cancer Res. 19, 4040–4045 (2013).

    Article  CAS  Google Scholar 

  13. Peifer, M. et al. Nat. Genet. 44, 1104–1110 (2012).

    Article  CAS  Google Scholar 

  14. Stephens, R.M. et al. Neuron 12, 691–705 (1994).

    Article  CAS  Google Scholar 

  15. Surks, H.K., Richards, C.T. & Mendelsohn, M.E. J. Biol. Chem. 278, 51484–51493 (2003).

    Article  CAS  Google Scholar 

  16. Soda, M. et al. Nature 448, 561–566 (2007).

    Article  CAS  Google Scholar 

  17. Busch, R., Doebele, R.C., Patil, N.S., Pashine, A. & Mellins, E.D. Curr. Opin. Immunol. 12, 99–106 (2000).

    Article  CAS  Google Scholar 

  18. Rikova, K. et al. Cell 131, 1190–1203 (2007).

    Article  CAS  Google Scholar 

  19. Awad, M.M. et al. N. Engl. J. Med. 369, 1173 (2013).

    Article  CAS  Google Scholar 

  20. Martin-Zanca, D., Hughes, S.H. & Barbacid, M. Nature 319, 743–748 (1986).

    Article  CAS  Google Scholar 

  21. Seo, J.S. et al. Genome Res. 22, 2109–2119 (2012).

    Article  CAS  Google Scholar 

  22. George, D.J. et al. Cancer Res. 59, 2395–2401 (1999).

    CAS  PubMed  Google Scholar 

  23. Cui, J.J. et al. J. Med. Chem. 54, 6342–6363 (2011).

    Article  CAS  Google Scholar 

  24. Gnirke, A. et al. Nat. Biotechnol. 27, 182–189 (2009).

    Article  CAS  Google Scholar 

  25. Li, H. et al. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  26. McKenna, A. et al. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  Google Scholar 

  27. Zhou, W. et al. Nature 462, 1070–1074 (2009).

    Article  CAS  Google Scholar 

  28. Berger, M.F. et al. Genome Res. 20, 413–427 (2010).

    Article  CAS  Google Scholar 

  29. Kim, D. et al. Genome Biol. 14, R36 (2013).

    Article  Google Scholar 

  30. Doebele, R.C. et al. Clin. Cancer Res. 18, 1472–1482 (2012).

    Article  CAS  Google Scholar 

  31. Helfrich, B.A. et al. Clin. Cancer Res. 12, 7117–7125 (2006).

    Article  CAS  Google Scholar 

  32. Davies, K.D. et al. Clin. Cancer Res. 18, 4570–4579 (2012).

    Article  CAS  Google Scholar 

  33. Marek, L. et al. Mol. Pharmacol. 75, 196–207 (2009).

    Article  CAS  Google Scholar 

  34. Pitts, T.M. et al. Front Pharmacol. 4, 35 (2013).

    Article  Google Scholar 

  35. Oie, H.K. et al. J. Cell Biochem. Suppl. 24, 24–31 (1996).

    Article  CAS  Google Scholar 

  36. Sasaki, T. et al. Cancer Res. 71, 6051–6060 (2011).

    Article  CAS  Google Scholar 

Download references

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).

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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.

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Correspondence to Pasi A Jänne or Robert C Doebele.

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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.

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Supplementary Tables 1–4 (PDF 261 kb)

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Vaishnavi, A., Capelletti, M., Le, A. et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19, 1469–1472 (2013). https://doi.org/10.1038/nm.3352

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