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Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression

Oncogene volume 35, pages 3587–3597 (2016)Cite this article

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Abstract

Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10–20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.

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References

  1. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139.

    Article  CAS  Google Scholar 

  2. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561–566.

    Article  CAS  Google Scholar 

  3. Meador CB, Micheel CM, Levy MA, Lovly CM, Horn L, Warner JL et al. Beyond histology: translating tumor genotypes into clinically effective targeted therapies. Clin Cancer Res 2014; 20: 2264–2275.

    Article  CAS  Google Scholar 

  4. Gandara DR, Hammerman PS, Sos ML, Lara PN Jr, Hirsch FR . Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res 2015; 21: 2236–2243.

    Article  CAS  Google Scholar 

  5. Dieci MV, Arnedos M, Andre F, Soria JC . Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov 2013; 3: 264–279.

    Article  CAS  Google Scholar 

  6. Brooks AN, Kilgour E, Smith PD . Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 2012; 18: 1855–1862.

    Article  CAS  Google Scholar 

  7. Dienstmann R, Rodon J, Prat A, Perez-Garcia J, Adamo B, Felip E et al. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann Oncol 2014; 25: 552–563.

    Article  CAS  Google Scholar 

  8. Weiss J, Sos ML, Seidel D, Peifer M, Zander T, Heuckmann JM et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010; 2: 62ra93.

    Article  CAS  Google Scholar 

  9. Dutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 2011; 6: e20351.

    Article  CAS  Google Scholar 

  10. Heist RS, Mino-Kenudson M, Sequist LV, Tammireddy S, Morrissey L, Christiani DC et al. FGFR1 amplification in squamous cell carcinoma of the lung. J Thorac Oncol 2012; 7: 1775–1780.

    Article  CAS  Google Scholar 

  11. Schildhaus HU, Heukamp LC, Merkelbach-Bruse S, Riesner K, Schmitz K, Binot E et al. Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer. Mod Pathol 2012; 25: 1473–1480.

    Article  CAS  Google Scholar 

  12. Kohler LH, Mireskandari M, Knosel T, Altendorf-Hofmann A, Kunze A, Schmidt A et al. FGFR1 expression and gene copy numbers in human lung cancer. Virchows Arch 2012; 461: 49–57.

    Article  CAS  Google Scholar 

  13. Kim HR, Kim DJ, Kang DR, Lee JG, Lim SM, Lee CY et al. Fibroblast growth factor receptor 1 gene amplification is associated with poor survival and cigarette smoking dosage in patients with resected squamous cell lung cancer. J Clin Oncol 2013; 31: 731–737.

    Article  Google Scholar 

  14. Tran TN, Selinger CI, Kohonen-Corish MR, McCaughan BC, Kennedy CW, O'Toole SA et al. Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer. Lung Cancer 2013; 81: 462–467.

    Article  Google Scholar 

  15. Seo AN, Jin Y, Lee HJ, Sun PL, Kim H, Jheon S et al. FGFR1 amplification is associated with poor prognosis and smoking in non-small-cell lung cancer. Virchows Arch 2014; 465: 547–558.

    Article  CAS  Google Scholar 

  16. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489: 519–525.

    Article  Google Scholar 

  17. Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R . The FGFR landscape in cancer: analysis of 4853 tumors by next generation sequencing. Clin Cancer Res 2015; e-pub ahead of print 15 September 2015.

  18. Nogova L, Sequist LV, Cassier PA, Hidalgo M, Delord JP, Schuler MH et al. Targeting FGFR1-amplified lung squamous cell carcinoma with the selective pan-FGFR inhibitor BGJ398. J Clin Oncol 2014; 32 (suppl): abstr 8034.

    Article  Google Scholar 

  19. Paik PK, Shen R, Ferry D, Soria JC, Mathewson A, Kilgour E et al. A phase 1b open-label multicenter study of AZD4547 in patients with advanced squamous cell lung cancers: Preliminary antitumor activity and pharmacodynamic data. J Clin Oncol 2014; 32 (suppl); abstr 8035.

    Article  Google Scholar 

  20. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–792.

    Article  CAS  Google Scholar 

  21. Engelman JA, Janne PA . Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2008; 14: 2895–2899.

    Article  Google Scholar 

  22. Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci USA 2009; 106: 19503–19508.

    Article  CAS  Google Scholar 

  23. Laplante M, Sabatini DM . mTOR signaling at a glance. J Cell Sci 2009; 122: 3589–3594.

    Article  CAS  Google Scholar 

  24. Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131: 1190–1203.

    Article  CAS  Google Scholar 

  25. McDermott U, Ames RY, Iafrate AJ, Maheswaran S, Stubbs H, Greninger P et al. Ligand-dependent platelet-derived growth factor receptor (PDGFR)-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors. Cancer Res 2009; 69: 3937–3946.

    Article  CAS  Google Scholar 

  26. Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008; 68: 9280–9290.

    Article  CAS  Google Scholar 

  27. Wilson TR, Lee DY, Berry L, Shames DS, Settleman J . Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell 2011; 20: 158–172.

    Article  CAS  Google Scholar 

  28. Hata AN, Engelman JA, Faber AC . The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics. Cancer Discov 2015; 5: 475–487.

    Article  CAS  Google Scholar 

  29. Wynes MW, Hinz TK, Gao D, Martini M, Marek LA, Ware KE et al. FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin Cancer Res 2014; 20: 3299–3309.

    Article  CAS  Google Scholar 

  30. Zhang J, Zhang L, Su X, Li M, Xie L, Malchers F et al. Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models. Clin Cancer Res 2012; 18: 6658–6667.

    Article  CAS  Google Scholar 

  31. Robertson KD . DNA methylation, methyltransferases, and cancer. Oncogene 2001; 20: 3139–3155.

    Article  CAS  Google Scholar 

  32. Montenegro MF, Sanchez-del-Campo L, Fernandez-Perez MP, Saez-Ayala M, Cabezas-Herrera J, Rodriguez-Lopez JN . Targeting the epigenetic machinery of cancer cells. Oncogene 2015; 34: 135–143.

    Article  CAS  Google Scholar 

  33. Guagnano V, Kauffmann A, Wohrle S, Stamm C, Ito M, Barys L et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012; 2: 1118–1133.

    Article  CAS  Google Scholar 

  34. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S et al. AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 2012; 72: 2045–2056.

    Article  CAS  Google Scholar 

  35. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16: 401–412.

    Article  CAS  Google Scholar 

  36. Terai H, Soejima K, Yasuda H, Nakayama S, Hamamoto J, Arai D et al. Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC. Mol Cancer Res 2013; 11: 759–767.

    Article  CAS  Google Scholar 

  37. Harbinski F, Craig VJ, Sanghavi S, Jeffery D, Liu L, Sheppard KA et al. Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discov 2012; 2: 948–959.

    Article  CAS  Google Scholar 

  38. Wang J, Mikse O, Liao RG, Li Y, Tan L, Janne PA et al. Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells. Oncogene 2015; 34: 2167–2177.

    Article  CAS  Google Scholar 

  39. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013; 31: 3997–4013.

    Article  Google Scholar 

  40. Pros E, Lantuejoul S, Sanchez-Verde L, Castillo SD, Bonastre E, Suarez-Gauthier A et al. Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer. Int J Cancer 2013; 133: 898–907.

    Article  CAS  Google Scholar 

  41. Malchers F, Dietlein F, Schottle J, Lu X, Nogova L, Albus K et al. Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer. Cancer Discov 2014; 4: 246–257.

    Article  CAS  Google Scholar 

  42. Turner N, Grose R . Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010; 10: 116–129.

    Article  CAS  Google Scholar 

  43. Kunii K, Davis L, Gorenstein J, Hatch H, Yashiro M, Di Bacco A et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res 2008; 68: 2340–2348.

    Article  CAS  Google Scholar 

  44. Herbst RS, Gandara DR, Hirsch FR, Redman MW, LeBlanc M, Mack PC et al. Lung master protocol (Lung-MAP)-a biomarker-driven protocol for accelerating development of therapies for squamous cell lung cancer: SWOG S1400. Clin Cancer Res 2015; 21: 1514–1524.

    Article  CAS  Google Scholar 

  45. Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E et al. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest 2011; 121: 4311–4321.

    Article  CAS  Google Scholar 

  46. Ooi A, Inokuchi M, Harada S, Inazawa J, Tajiri R, Kitamura SS et al. Gene amplification of ESR1 in breast cancers—fact or fiction? A fluorescence in situ hybridization and multiplex ligation-dependent probe amplification study. J Pathol 2012; 227: 8–16.

    Article  CAS  Google Scholar 

  47. Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 2015; 6: 6377.

    Article  CAS  Google Scholar 

  48. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2: 401–404.

    Article  Google Scholar 

  49. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6: pl1.

    Article  Google Scholar 

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Acknowledgements

We thank Dr Shuta Tomida at Okayama University for his assistance with the statistics. This work was supported by Grants-in-Aid for Scientific Research (H Ebi, 26830105 and S Yano, 21390256), Scientific Research on Innovative Areas ‘Integrative Research on Cancer Microenvironment Network’ (H Ebi and S Yano, 22112010A01) and Grant-in-Aid for Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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  1. H Kotani and H Ebi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    H Kotani, H Ebi, H Kitai, S Nanjo, K Kita & S Yano

  2. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    T G Huynh & M Mino-Kenudson

  3. Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

    A Ooi

  4. VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    A C Faber

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Kotani, H., Ebi, H., Kitai, H. et al. Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression. Oncogene 35, 3587–3597 (2016). https://doi.org/10.1038/onc.2015.426

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