Skip to main content

Thank you for visiting 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.

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer


Human non–small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: AXL is overexpressed in EGFR-mutant NSCLC tumor xenografts with acquired resistance to erlotinib.
Figure 2: AXL overexpression is necessary for acquired resistance to erlotinib treatment in EGFR-mutant NSCLC tumors in vivo.
Figure 3: AXL upregulation is necessary and sufficient for acquired resistance to erlotinib in EGFR-mutant NSCLC cellular models.
Figure 4: AXL-mediated erlotinib resistance occurs in association with EMT in EGFR-mutant NSCLC cellular models.
Figure 5: AXL upregulation occurs in human EGFR-mutant NSCLCs with acquired resistance to EGFR TKIs.

Accession codes

Primary accessions

Gene Expression Omnibus


  1. Paez, J.G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).

    Article  CAS  Google Scholar 

  2. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. USA 101, 13306–13311 (2004).

    Article  CAS  Google Scholar 

  3. Lynch, T.J. et al. 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 (2004).

    Article  CAS  Google Scholar 

  4. Sordella, R., Bell, D.W., Haber, D.A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163–1167 (2004).

    Article  CAS  Google Scholar 

  5. Jänne, P.A., Gray, N. & Settleman, J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat. Rev. Drug Discov. 8, 709–723 (2009).

    Article  Google Scholar 

  6. Gazdar, A.F. Personalized medicine and inhibition of EGFR signaling in lung cancer. N. Engl. J. Med. 361, 1018–1020 (2009).

    Article  CAS  Google Scholar 

  7. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article  CAS  Google Scholar 

  8. Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73 (2005).

    Article  Google Scholar 

  9. Engelman, J.A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).

    Article  CAS  Google Scholar 

  10. Turke, A.B. et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010).

    Article  CAS  Google Scholar 

  11. Bivona, T.G. et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011).

    Article  CAS  Google Scholar 

  12. Arcila, M.E. et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid–based assay. Clin. Cancer Res. 17, 1169–1180 (2011).

    Article  CAS  Google Scholar 

  13. Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA 104, 20932–20937 (2007).

    Article  CAS  Google Scholar 

  14. Sequist, L.V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).

    Article  Google Scholar 

  15. Linger, R.M., Keating, A.K., Earp, H.S. & Graham, D.K. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Expert Opin. Ther. Targets 14, 1073–1090 (2010).

    Article  CAS  Google Scholar 

  16. Keating, A.K. et al. Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Mol. Cancer Ther. 9, 1298–1307 (2010).

    Article  CAS  Google Scholar 

  17. Vuoriluoto, K. et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 30, 1436–1448 (2011).

    Article  CAS  Google Scholar 

  18. Suda, K. et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor–mutant lung cancer cell line with acquired resistance to erlotinib. J. Thorac. Oncol. 6, 1152–1161 (2011).

    Article  Google Scholar 

  19. Ye, X. et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene 29, 5254–5264 (2010).

    Article  CAS  Google Scholar 

  20. Qian, F. et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 69, 8009–8016 (2009).

    Article  CAS  Google Scholar 

  21. Yun, C.H. et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. USA 105, 2070–2075 (2008).

    Article  CAS  Google Scholar 

  22. Polyak, K. & Weinberg, R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273 (2009).

    Article  CAS  Google Scholar 

  23. Jackman, D. et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J. Clin. Oncol. 28, 357–360 (2010).

    Article  CAS  Google Scholar 

  24. Burchert, A., Attar, E.C., McCloskey, P., Fridell, Y.W. & Liu, E.T. Determinants for transformation induced by the Axl receptor tyrosine kinase. Oncogene 16, 3177–3187 (1998).

    Article  CAS  Google Scholar 

  25. Tai, K.Y., Shieh, Y.S., Lee, C.S., Shiah, S.G. & Wu, C.W. Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-κB and Brg-1. Oncogene 27, 4044–4055 (2008).

    Article  CAS  Google Scholar 

  26. Azumi, N. & Battifora, H. The distribution of vimentin and keratin in epithelial and nonepithelial neoplasms. A comprehensive immunohistochemical study on formalin- and alcohol-fixed tumors. Am. J. Clin. Pathol. 88, 286–296 (1987).

    Article  CAS  Google Scholar 

  27. Chitale, D. et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene 28, 2773–2783 (2009).

    Article  CAS  Google Scholar 

  28. Rosell, R., Wei, J. & Taron, M. Circulating microRNA signatures of tumor-derived exosomes for early diagnosis of non-small-cell lung cancer. Clin. Lung Cancer 10, 8–9 (2009).

    Article  CAS  Google Scholar 

  29. Brevet, M., Arcila, M. & Ladanyi, M. Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. J. Mol. Diagn. 12, 169–176 (2010).

    Article  CAS  Google Scholar 

Download references


The authors thank K. Shokat for assistance with structural modeling of the AXL gatekeeper mutation, W. Polkinghorn, J. Wongvipat and E. Chan for advice and technical assistance and S. Edelheit of the Case Genomics Center for technical assistance. This work was supported by the Korean Health Technology R&D Project (grant A102059 to J.C.L.), the US National Institutes of Health (K08 1K08CA154787 to T.G.B. and P01 CA129243 to M.L.), a Uniting Against Lung Cancer Research Award, a National Lung Cancer Partnership Young Investigator Award (to T.G.B.), a grant from the La Caixa Foundation (to R.R.) and an American Cancer Society Research Scholar Grant (RSG-08-303-01 to B.H.).

Author information

Authors and Affiliations



Z.Z., J.C.L., L.L., V.A., T.L., M.A.-R., X.W., A.D.L., J.K.R., Y.J.C., C.-M.C., Y.S.P., S.-W.K., D.H.L., J.-S.L., P.M. and T.G.B. performed in vitro experiments. J.C.L., V.O., S.J.J., Y.S.P. and C.C. analyzed clinical specimens. M.A. and T.G.B. analyzed clinical data. P.M. and T.G.B. performed in vivo experiments. W.S.K., P.C.M., M.L., T.J.B., V.A.M., C.S., P.M., M.T., R.R., B.H. and T.G.B. analyzed in vitro and in vivo data. B.H. and T.G.B. wrote the manuscript.

Corresponding authors

Correspondence to Balazs Halmos or Trever G Bivona.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 and Supplementary Tables 4 and 5 (PDF 11391 kb)

Supplementary Table 1

Gene expression changes observed in erlotinib resistant HCC827 tumor xenografts by combined analysis. (XLS 117 kb)

Supplementary Table 2

Gene expression changes observed in erlotinib resistant HCC827 tumor xenografts. (XLS 4588 kb)

Supplementary Table 3

Gene expression changes observed in erlotinib resistant HCC827 cell lines. (XLS 203 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhang, Z., Lee, J., Lin, L. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44, 852–860 (2012).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer