Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer

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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Figure 1: Exceptional response to an IGF-1R inhibitor before ALK TKI therapy in a patient with ALK+ lung cancer.
Figure 2: Combination therapy with an IGF-1R inhibitor plus an ALK inhibitor promotes cooperative inhibition of cell growth in TKI-sensitive ALK+ lung cancer cells.
Figure 3: IRS-1 knockdown impairs downstream signaling and blocks proliferation of ALK+ lung cancer cells.
Figure 4: The IGF-1R pathway is activated in models of ALK TKI resistance.
Figure 5: Increased IGF-1R and IRS-1 levels in patient biopsy samples at the time of acquired resistance to crizotinib.
Figure 6: The second-generation ALK inhibitor LDK-378 blocks the phosphorylation of both ALK and IGF-1R.

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References

  1. 1

    Grande, E., Bolos, M.V. & Arriola, E. Targeting oncogenic ALK: a promising strategy for cancer treatment. Mol. Cancer Ther. 10, 569–579 (2011).

    CAS  Article  Google Scholar 

  2. 2

    Camidge, D.R. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13, 1011–1019 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Katayama, R. et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci. Transl. Med. 4, 120ra117 (2012).

    Article  Google Scholar 

  4. 4

    Doebele, R.C. et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin. Cancer Res. 18, 1472–1482 (2012).

    CAS  Article  Google Scholar 

  5. 5

    Lovly, C.M. & Pao, W. Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci. Transl. Med. 4, 120ps122 (2012).

    Article  Google Scholar 

  6. 6

    Tanizaki, J. et al. Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK–positive non-small cell lung cancer. Clin. Cancer Res. 18, 6219–6226 (2012).

    CAS  Article  Google Scholar 

  7. 7

    Iyer, G. et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 338, 221 (2012).

    CAS  Article  Google Scholar 

  8. 8

    Shaw, A.T. et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J. Clin. Oncol. 27, 4247–4253 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Boik, J.C., Newman, R.A. & Boik, R.J. Quantifying synergism/antagonism using nonlinear mixed-effects modeling: a simulation study. Stat. Med. 27, 1040–1061 (2008).

    Article  Google Scholar 

  10. 10

    Mulvihill, M.J. et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med. Chem. 1, 1153–1171 (2009).

    CAS  Article  Google Scholar 

  11. 11

    Metz, H.E. & Houghton, A.M. Insulin receptor substrate regulation of phosphoinositide 3-kinase. Clin. Cancer Res. 17, 206–211 (2011).

    CAS  Article  Google Scholar 

  12. 12

    Yang, X. et al. Using tandem mass spectrometry in targeted mode to identify activators of class IA PI3K in cancer. Cancer Res. 71, 5965–5975 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Chen, Z. et al. Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res. 70, 9827–9836 (2010).

    CAS  Article  Google Scholar 

  14. 14

    Lovly, C.M. et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res. 71, 4920–4931 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Katayama, R. et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc. Natl. Acad. Sci. USA 108, 7535–7540 (2011).

    CAS  Article  Google Scholar 

  16. 16

    Guix, M. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest. 118, 2609–2619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Cortot, A.B. et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 73, 834–843 (2013).

    CAS  Article  Google Scholar 

  18. 18

    García-Echeverria, C. et al. In vivo antitumor activity of NVP-AEW541—a novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5, 231–239 (2004).

    Article  Google Scholar 

  19. 19

    Morgillo, F. et al. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin. Cancer Res. 13, 2795–2803 (2007).

    CAS  Article  Google Scholar 

  20. 20

    Vazquez-Martin, A. et al. IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations. Sci. Rep. 3, 2560 (2013).

    Article  Google Scholar 

  21. 21

    Chmielecki, J. et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci. Transl. Med. 3, 90ra59 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Ohashi, K. et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc. Natl. Acad. Sci. USA 109, E2127–E2133 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Suehara, Y. et al. Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin. Cancer Res. 18, 6599–6608 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Shaw, A.T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 1189–1197 (2014).

    CAS  Article  Google Scholar 

  25. 25

    Galkin, A.V. et al. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. Proc. Natl. Acad. Sci. USA 104, 270–275 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Morris, S.W. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263, 1281–1284 (1994).

    CAS  Article  Google Scholar 

  27. 27

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Gainor, J.F. et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin. Cancer Res. 19, 4273–4281 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Dunning, M.J., Smith, M.L., Ritchie, M.E. & Tavare, S. Beadarray: R classes and methods for Illumina bead-based data. Bioinformatics 23, 2183–2184 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Su, Z. et al. A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. J. Mol. Diagn. 13, 74–84 (2011).

    CAS  Article  Google Scholar 

Download references

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.

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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.

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Correspondence to Christine M Lovly.

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Lovly, C., McDonald, N., Chen, H. et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer. Nat Med 20, 1027–1034 (2014). https://doi.org/10.1038/nm.3667

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