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.

  • Commentary
  • Published:

TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition

Oncogene volume 35, pages 2684–2686 (2016)Cite this article

Subjects

Abstract

TAM (Tyro3-Axl-Mer) receptor tyrosine kinases and Met are implicated in several hallmarks of cancer progression including sustained angiogenesis, enhanced motility, tissue invasion and acquisition of metastatic potential through the upregulation of epithelial-to-mesenchymal transition. Increasing evidence has confirmed Axl and Met as emerging central drivers of adaptive resistance to targeted therapies across a wide variety of cancers. In this issue of Oncogene, Zhou et al. describe the mechanisms linking Axl and Met activation to acquired resistance to sunitinib in renal cell carcinoma (RCC), providing a pre-clinical rationale for the development of Axl and Met inhibitors including cabozantinib in anti-angiogenic resistant RCC.

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

Relevant articles

Open Access articles citing this article.

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

References

  1. Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.

    Article  Google Scholar 

  2. Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14: 4726–4734.

    Article  CAS  Google Scholar 

  3. Ciccarese C, Massari F, Santoni M, Heng DY, Sotte V, Brunelli M et al. New molecular targets in non clear renal cell carcinoma: An overview of ongoing clinical trials. Cancer Treat Rev 2015; 41: 614–622.

    Article  CAS  Google Scholar 

  4. Grunwald V, Merseburger AS . The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors—is there more to come? Eur J Cancer 2013; 49: 2504–2511.

    Article  CAS  Google Scholar 

  5. Faivre S, Demetri G, Sargent W, Raymond E . Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007; 6: 734–745.

    Article  CAS  Google Scholar 

  6. Linger RM, Keating AK, Earp HS, Graham DK . Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Expert Opin Ther Targets 2010; 14: 1073–1090.

    Article  CAS  Google Scholar 

  7. Vuoriluoto K, Haugen H, Kiviluoto S, Mpindi JP, Nevo J, Gjerdrum C et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 2011; 30: 1436–1448.

    Article  CAS  Google Scholar 

  8. Burchert A, Attar EC, McCloskey P, Fridell YW, Liu ET . Determinants for transformation induced by the Axl receptor tyrosine kinase. Oncogene 1998; 16: 3177–3187.

    Article  CAS  Google Scholar 

  9. Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 2012; 22: 2109–2119.

    Article  CAS  Google Scholar 

  10. Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA 2014; 111: 13373–13378.

    Article  CAS  Google Scholar 

  11. Yoshida T, Zhang G, Smith MA, Lopez AS, Bai Y, Li J et al. Tyrosine phosphoproteomics identifies both codrivers and cotargeting strategies for T790M-related EGFR-TKI resistance in non-small cell lung cancer. Clin Cancer Res 2014; 20: 4059–4074.

    Article  CAS  Google Scholar 

  12. Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Luthar N et al. AXL mediates resistance to cetuximab therapy. Cancer Res 2014; 74: 5152–5164.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Park IK, Mundy-Bosse B, Whitman SP, Zhang X, Warner SL, Bearss DJ et al. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia e-pub ahead of print 19 June 2015.

  15. Dufies M, Jacquel A, Belhacene N, Robert G, Cluzeau T, Luciano F et al. Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells. Oncotarget 2011; 2: 874–885.

    Article  Google Scholar 

  16. Singh A, Settleman J . EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29: 4741–4751.

    Article  CAS  Google Scholar 

  17. Scagliotti GV, Novello S, von Pawel J . The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev 2013; 39: 793–801.

    Article  CAS  Google Scholar 

  18. Graham DK, DeRyckere D, Davies KD, Earp HS . The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 2014; 14: 769–785.

    Article  CAS  Google Scholar 

  19. Kirane A, Ludwig KF, Sorrelle N, Haaland G, Sandal T, Ranaweera R et al. Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis. Cancer Res e-pub ahead of print 23 July 2015.

  20. Choueiri TK, Pal SK, McDermott DF, Morrissey S, Ferguson KC, Holland J et al. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol 2014; 25: 1603–1608.

    Article  CAS  Google Scholar 

  21. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 2013; 14: 55–63.

    Article  CAS  Google Scholar 

  22. Watermann I, Schmitt B, Stellmacher F, Muller J, Gaber R, Kugler C et al. Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation? Diagn Pathol 2015; 10: 130.

    Article  CAS  Google Scholar 

  23. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–892.

    Article  CAS  Google Scholar 

  24. Kim MS, Zhong Y, Yachida S, Rajeshkumar NV, Abel ML, Marimuthu A et al. Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics. Mol Cell Proteomics 2014; 13: 2803–2811.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

DJP is supported by grant funding from Action Against Cancer and the Academy of Medical Sciences. JS is supported by grant funding from Action Against Cancer and the Hilary Craft Foundation.

Author information

Authors and Affiliations

  1. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK

    D J Pinato & J Stebbing

  2. Department of Medical Oncology, Guy's Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

    S Chowdhury

Authors
  1. D J Pinato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Chowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Stebbing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D J Pinato.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pinato, D., Chowdhury, S. & Stebbing, J. TAMing resistance to multi-targeted kinase inhibitors through Axl and Met inhibition. Oncogene 35, 2684–2686 (2016). https://doi.org/10.1038/onc.2015.374

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.374

This article is cited by

Search

Advanced search

Quick links