Abstract

Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion–positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R–IRS-1 pathway in both ALK TKI–sensitive and ALK TKI–resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

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Acknowledgements

This work was supported by the Vanderbilt-Ingram Cancer Center Core grant (P30-CA68485), a career development award from the Vanderbilt Specialized Program of Research Excellence in Lung Cancer grant (CA90949), US National Cancer Institute grants R01CA121210 and P01CA129243 and the Joyce Family Foundation. C.M.L. was additionally supported by a US National Institutes of Health (NIH) K12 training grant (K12 CA9060625), an American Society of Clinical Oncology Young Investigator Award, a Uniting Against Lung Cancer grant and a Damon Runyon Clinical Investigator Award. C.M.L. was the Carol and Jim O'Hare chief fellow from 7/1/2011 through 6/30/2012. L.C.H. and R.B. were supported by the Deutsche Forschungsgemeinschaft (SFB 832, Tumormicromilieu) and the German Cancer Aid (Center for Integrated Oncology (CIO) Köln-Bonn). M. Bos was supported by the European Regional Development Fund grant number FKZ:005-111-0027. G.M.W. was supported by the Victorian Cancer Agency grant TS10_01. K.-K.W. is supported by the NIH CA122794, CA140594, CA163896, CA166480 and CA154303 grants. P.K.P. was supported by a Uniting Against Lung Cancer grant. R.K.T. is supported by the EU-Framework Programme CURELUNG (HEALTH-F2-2010-258677), the Deutsche Forschungsgemeinschaft through TH1386/3-1 and SFB832 (TP6), the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grant 01GS08100) and the Deutsche Krebshilfe as part of the Oncology Centers of Excellence funding program. S.P. was supported by a grant from the Rudolph Becker Foundation. J.W. was supported by the German Cancer Aid (CIO Köln-Bonn), the Federal Ministry of Education and Research (NGFNplus) and the Ministry of Economy, Energy, Industry and Craft of North Rhine-Westfalia (NRW) in the PerMed NRW framework program. Z.Z. was supported by NIH R01LM011177. We thank J. Sosman and C. Arteaga for their critical review of this manuscript, C. Liang (Xcovery) for providing X-376 and A. Nashabi for administrative assistance. Australian specimens were processed by the Victorian Cancer Biobank. The human anaplastic lymphoma cell line, SUDHL-1, was a generous gift from S. Morris of St. Jude Children's Research Hospital.

Author information

Affiliations

  1. Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

    • Christine M Lovly
    • , Nerina T McDonald
    • , Yingjun Yan
    • , Hailing Jin
    • , Monica Red-Brewer
    • , Leora Horn
    •  & William Pao
  2. Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.

    • Heidi Chen
    • , Xi Chen
    •  & Pengcheng Lu
  3. Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.

    • Sandra Ortiz-Cuaran
    • , Marc Bos
    •  & Roman K Thomas
  4. Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.

    • Lukas C Heukamp
    • , Alexandra Florin
    • , Luka Ozretić
    • , Reinhard Buettner
    •  & Roman K Thomas
  5. New Oncology, Cologne, Germany.

    • Lukas C Heukamp
  6. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Diana Lim
    • , Lu Wang
    • , Yoshiyuki Suehara
    •  & Marc Ladanyi
  7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Zhao Chen
    •  & Kwok-Kin Wong
  8. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Paul K Paik
  9. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Ronglai Shen
  10. Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.

    • Sascha Ansén
    • , Marc Bos
    • , Jürgen Wolf
    •  & Masyar Gardizi
  11. Department of Prostate Cancer Research, Institute of Pathology, Center of Integrated Oncology Köln-Bonn, University Hospital of Bonn, Bonn, Germany.

    • Sven Perner
  12. Department of Pathology, Hospital Merheim, Cologne, Germany.

    • Michael Brockmann
  13. Department of Surgery, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria, Australia.

    • Gavin M Wright
  14. Division of Hematology and Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia.

    • Benjamin Solomon
  15. Department of Anatomical Pathology, St. Vincent's Hospital, Melbourne, Victoria, Australia.

    • Prudence A Russell
  16. Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.

    • Toni-Maree Rogers
  17. Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Rudy Tieu
    •  & Elisa de Stanchina
  18. Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.

    • Qingguo Wang
    •  & Zhongming Zhao
  19. Department of Medicine, UT Southwestern School of Medicine, Dallas, Texas, USA.

    • David H Johnson

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Contributions

C.M.L. and W.P. conceived the project and wrote the manuscript. C.M.L., N.T.M., Y.Y., H.J. and M.R.-B. performed the molecular biology experiments. H.C., P.L., X.C. and R.S. performed the statistical analyses. S.O.-C., L.C.H., A.F. and R.K.T. performed all the IGF-1R and IRS-1 immunohistochemistry experiments. S.O.-C., L.O., P.K.P., R.B., S.A., S.P., M. Brockmann, M. Bos, J.W., M.G., G.M.W., B.S., P.A.R., T.-M.R. and R.K.T. provided clinical samples. D.H.J. and L.H. provided clinical care for the index patient. Z.C. and K.-K.W. provided the EML4-ALK E13;A20 transgenic mice. D.L., L.W., Y.S. and M.L. performed all the FISH and NanoString experiments. R.T. and E.d.S. performed the xenograft studies. Q.W. and Z.Z. analyzed the whole-genome sequencing data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christine M Lovly.

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DOI

https://doi.org/10.1038/nm.3667

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