Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

Oncogene volume 29, pages 5254–5264 (2010)Cite this article

Subjects

Abstract

Axl is expressed in various types of cancer and is involved in multiple processes of tumorigenesis, including promoting tumor cell growth, migration, invasion, metastasis as well as angiogenesis. To evaluate further the mechanisms involved in the expression/activation of Axl in various aspects of tumorigenesis, especially its roles in modulating tumor stromal functions, we have developed a phage-derived mAb (YW327.6S2) that recognizes both human and murine Axl. YW327.6S2 binds to both human and murine Axl with high affinity. It blocks the ligand Gas6 binding to the receptor, downregulates receptor expression, inhibits receptor activation and downstream signaling. In A549 non-small-cell lung cancer (NSCLC) and MDA-MB-231 breast cancer models, YW327.6S2 attenuates xenograft tumor growth and potentiates the effect of anti-VEGF treatment. In NSCLC models, YW327.6S2 also enhances the effect of erlotinib and chemotherapy in reducing tumor growth. Furthermore, YW327.6S2 reduces the metastasis of MDA-MB-231 breast cancer cells to distant organs. YW327.6S2 induces tumor cell apoptosis in NSCLC, reduces tumor-associated vascular density and inhibits the secretion of inflammatory cytokines and chemokines from tumor-associated macrophages in the breast cancer model. In conclusion, anti-Axl mAb can enhance the therapeutic efficacy of anti-VEGF, EGFR small-molecule inhibitors as well as chemotherapy. Axl mAb affects not only tumor cells but also tumor stroma through its modulation of tumor-associated vasculature and immune cell functions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Balkwill F, Charles KA, Mantovani A . (2005). Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7: 211–217.

    Article  CAS  Google Scholar 

  • Balkwill F, Mantovani A . (2001). Inflammation and cancer: back to Virchow? Lancet 357: 539–545.

    Article  CAS  Google Scholar 

  • Berclaz G, Altermatt HJ, Rohrbach V, Kieffer I, Dreher E, Andres AC . (2001). Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. Ann Oncol 12: 819–824.

    Article  CAS  Google Scholar 

  • Brey EM, Lalani Z, Johnston C, Wong M, McIntire LV, Duke PJ et al. (2003). Automated selection of DAB-labeled tissue for immunohistochemical quantification. J Histochem Cytochem 51: 575–584.

    Article  CAS  Google Scholar 

  • Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL et al. (1992). Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289.

    Article  CAS  Google Scholar 

  • Chung BI, Malkowicz SB, Nguyen TB, Libertino JA, McGarvey TW . (2003). Expression of the proto-oncogene Axl in renal cell carcinoma. DNA Cell Biol 22: 533–540.

    Article  CAS  Google Scholar 

  • Coussens LM, Werb Z . (2002). Inflammation and cancer. Nature 420: 860–867.

    Article  CAS  Google Scholar 

  • Craven RJ, Xu LH, Weiner TM, Fridell YW, Dent GA, Srivastava S et al. (1995). Receptor tyrosine kinases expressed in metastatic colon cancer. Int J Cancer 60: 791–797.

    Article  CAS  Google Scholar 

  • Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS et al. (2005). Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23: 5900–5909.

    Article  CAS  Google Scholar 

  • Giaccone G . (2005). Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23: 3235–3242.

    Article  CAS  Google Scholar 

  • Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T et al. (2010). Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci USA 107: 1124–1129.

    Article  CAS  Google Scholar 

  • Haghnegahdar H, Du J, Wang D, Strieter RM, Burdick MD, Nanney LB et al. (2000). The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma. J Leukoc Biol 67: 53–62.

    Article  CAS  Google Scholar 

  • Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W et al. (2010). R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res 70: 1544–1554.

    Article  CAS  Google Scholar 

  • Holland SJ, Powell MJ, Franci C, Chan EW, Friera AM, Atchison RE et al. (2005). Multiple roles for the receptor tyrosine kinase axl in tumor formation. Cancer Res 65: 9294–9303.

    Article  CAS  Google Scholar 

  • Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT et al. (2008). Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett 268: 314–324.

    Article  CAS  Google Scholar 

  • Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Stefanova N et al. (2008). Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res 14: 130–138.

    Article  CAS  Google Scholar 

  • Ito T, Ito M, Naito S, Ohtsuru A, Nagayama Y, Kanematsu T et al. (1999). Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma. Thyroid 9: 563–567.

    Article  CAS  Google Scholar 

  • Janssen JW, Schulz AS, Steenvoorden AC, Schmidberger M, Strehl S, Ambros PF et al. (1991). A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene 6: 2113–2120.

    CAS  Google Scholar 

  • Koorstra JB, Karikari CA, Feldmann G, Bisht S, Rojas PL, Offerhaus GJ et al. (2009). The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther 8: 618–626.

    Article  CAS  Google Scholar 

  • Lai C, Lemke G . (1991). An extended family of protein-tyrosine linase genes differentially expressed in the vertebrate nervous system. Neuron 6: 691–704.

    Article  CAS  Google Scholar 

  • Lee CV, Liang WC, Dennis MS, Eigenbrot C, Sidhu SS, Fuh G . (2004). High-affinity human antibodies from phage-displayed synthetic Fab libraries with a single framework scaffold. J Mol Biol 340: 1073–1093.

    Article  CAS  Google Scholar 

  • Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J et al. (2009). Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene 28: 3442–3455.

    Article  CAS  Google Scholar 

  • Liang WC, Wu X, Peale FV, Lee CV, Meng YG, Gutierrez J et al. (2006). Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF. J Biol Chem 281: 951–961.

    Article  CAS  Google Scholar 

  • Liang WC, Dennis MS, Stawicki S, Chanthery Y, Pan Q, Chen Y et al. (2007). Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J Mol Biol 366: 815–829.

    Article  CAS  Google Scholar 

  • Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R et al. (2009). Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 69: 6871–6878.

    Article  CAS  Google Scholar 

  • Loges S, Schmidt T, Tjwa M, van Geyte K, Lievens D, Lutgens E et al. (2010). Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood 115: 2264–2273.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K et al. (2007). A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 26: 3909–3919.

    Article  CAS  Google Scholar 

  • Meric F, Lee WP, Sahin A, Zhang H, Kung HJ, Hung MC . (2002). Expression profile of tyrosine kinases in breast cancer. Clin Cancer Res 8: 361–367.

    CAS  Google Scholar 

  • O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C et al. (1991). Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol 11: 5016–5031.

    Article  CAS  Google Scholar 

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.

    Article  CAS  Google Scholar 

  • Pollard JW . (2004). Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4: 71–78.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC . (2005). Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J Cell Physiol 204: 36–44.

    Article  CAS  Google Scholar 

  • Sandley A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A et al. (2006). Palitaxel–carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355: 2542–2550.

    Article  Google Scholar 

  • Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS et al. (2005). Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia 7: 1058–1064.

    Article  CAS  Google Scholar 

  • Sidhu SS, Li B, Chen Y, Fellouse FA, Eigenbrot C, Fuh G . (2004). Phage-displayed antibody libraries of synthetic heavy chain complementarity determining regions. J Mol Biol 338: 299–310.

    Article  CAS  Google Scholar 

  • Sun W, Fujimoto J, Tamaya T . (2004). Coexpression of Gas6/Axl in human ovarian cancers. Oncology 66: 450–457.

    Article  CAS  Google Scholar 

  • Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW . (2008). Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene 27: 4044–4055.

    Article  CAS  Google Scholar 

  • Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J et al. (2005). Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353: 133–144.

    Article  CAS  Google Scholar 

  • Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-Kobligk H et al. (2006). Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci USA 103: 5799–5804.

    Article  CAS  Google Scholar 

  • Wu CW, Li AF, Chi CW, Lai CH, Huang CL, Lo SS et al. (2002). Clinical significance of AXL kinase family in gastric cancer. Anticancer Res 22: 1071–1078.

    CAS  Google Scholar 

  • Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L et al. (2005). Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 11: 8686–8698.

    Article  CAS  Google Scholar 

  • Zhang YX, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L et al. (2008). AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res 68: 1905–1915.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Jiping Zha for developing the dual anti-Axl/CD68 IHC protocol.

Author information

Author notes

  1. X Ye and Y Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA

    X Ye, Y Li & L Pei

  2. Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, USA

    S Stawicki & Y Wu

  3. Department of Pathology, Genentech Inc., South San Francisco, CA, USA

    S Couto & J Eastham-Anderson

  4. Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA, USA

    D Kallop & R Weimer

Authors
  1. X Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Stawicki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Couto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Eastham-Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Kallop
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Weimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Pei.

Ethics declarations

Competing interests

The authors declare no conflict of interest. The authors are all employees of Genentech.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ye, X., Li, Y., Stawicki, S. et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene 29, 5254–5264 (2010). https://doi.org/10.1038/onc.2010.268

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.268

Keywords

This article is cited by

Search

Advanced search

Quick links