Skip to main content
SpringerLink
Log in

Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Lenvatinib is a long-awaited alternative to sorafenib for the first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to lenvatinib has also become a major obstacle to improving the prognosis of HCC patients. The underlying molecular mechanisms contributing to lenvatinib resistance in HCC are largely unknown. HGF/c-MET axis activation is related to tumor progression and several hallmarks of cancer and is considered as the key contributor to drug resistance. In the present study, we focused on the role of the HGF/c-MET axis in mediating lenvatinib resistance in HCC cells. We showed that HGF reduced the antiproliferative, proapoptotic, and anti-invasive effects of lenvatinib on HCC cells with high c-MET expression but did not significantly affect HCC cells with low c-MET expression. The c-MET inhibitor PHA-665752 rescued HCC cells from HGF-induced lenvatinib resistance. Furthermore, HGF/c-MET activated the downstream PI3K/AKT and MAPK/ERK pathways and promoted epithelial–mesenchymal transition (EMT) in HCC cells. Collectively, our results suggested that combining lenvatinib treatment with a c-MET inhibitor may improve its systemic therapeutic efficacy in HCC patients with high c-MET expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kanwal F, Singal AG. Surveillance for hepatocellular carcinoma: current best practice and future direction. Gastroenterology. 2019;157(1):54–64. https://doi.org/10.1053/j.gastro.2019.02.049.

    Article  PubMed  Google Scholar 

  2. Pinter M, Peck-Radosavljevic M. Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther. 2018;48(6):598–609. https://doi.org/10.1111/apt.14913.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33(2):172–9. https://doi.org/10.1200/JCO.2013.54.3298.

    Article  CAS  PubMed  Google Scholar 

  4. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31(32):4067–75. https://doi.org/10.1200/JCO.2012.45.8372.

    Article  CAS  PubMed  Google Scholar 

  5. Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33(6):559–66. https://doi.org/10.1200/JCO.2013.53.7746.

    Article  CAS  PubMed  Google Scholar 

  6. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24. https://doi.org/10.1200/JCO.2012.48.4410.

    Article  CAS  PubMed  Google Scholar 

  7. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312(1):57–67. https://doi.org/10.1001/jama.2014.7189.

    Article  CAS  PubMed  Google Scholar 

  8. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–73. https://doi.org/10.1016/S0140-6736(18)30207-1.

    Article  CAS  PubMed  Google Scholar 

  9. Bangaru S, Marrero JA, Singal AG. Review article: new therapeutic interventions for advanced hepatocellular carcinoma. Aliment Pharmacol Ther. 2020;51(1):78–89. https://doi.org/10.1111/apt.15573.

    Article  CAS  PubMed  Google Scholar 

  10. Moosavi F, Giovannetti E, Saso L, Firuzi O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit Rev Clin Lab Sci. 2019;56(8):533–66. https://doi.org/10.1080/10408363.2019.1653821.

    Article  CAS  PubMed  Google Scholar 

  11. You WK, McDonald DM. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep. 2008;41(12):833–9. https://doi.org/10.5483/bmbrep.2008.41.12.833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011;3(1 Suppl):S7–S19. https://doi.org/10.1177/1758834011422556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kim KH, Kim H. Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy. Exp Mol Med. 2017;49(3):e307. https://doi.org/10.1038/emm.2017.17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang X, Gan G, Wang X, Xu T, Xie W. The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy. 2019;15(7):1258–79. https://doi.org/10.1080/15548627.2019.1580105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Al-Salama ZT, Syed YY, Scott LJ. Lenvatinib: a review in hepatocellular carcinoma. Drugs. 2019;79(6):665–74. https://doi.org/10.1007/s40265-019-01116-x.

    Article  CAS  PubMed  Google Scholar 

  16. Raghav KP, Gonzalez-Angulo AM, Blumenschein GR Jr. Role of HGF/MET axis in resistance of lung cancer to contemporary management. Transl Lung Cancer Res. 2012;1(3):179–93. https://doi.org/10.3978/j.issn.2218-6751.2012.09.04.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jeng KS, Chang CF, Jeng WJ, Sheen IS, Jeng CJ. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol. 2015;94(3):337–47. https://doi.org/10.1016/j.critrevonc.2015.01.009.

    Article  PubMed  Google Scholar 

  18. Kim JH, Kim HS, Kim BJ, Jang HJ, Lee J. Prognostic value of c-Met overexpression in hepatocellular carcinoma: a meta-analysis and review. Oncotarget. 2017;8(52):90351–7. https://doi.org/10.18632/oncotarget.20087.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ, et al. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 2011;337(1):155–61. https://doi.org/10.1124/jpet.110.175786.

    Article  CAS  PubMed  Google Scholar 

  20. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016;15:18. https://doi.org/10.1186/s12943-016-0502-x.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010;29(34):4741–51. https://doi.org/10.1038/onc.2010.215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. van Malenstein H, Dekervel J, Verslype C, Van Cutsem E, Windmolders P, Nevens F, et al. Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett. 2013;329(1):74–83. https://doi.org/10.1016/j.canlet.2012.10.021.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Medical Science and Technology Research Fund of Guangdong Province, China (Grant Number A2017387).

Author information

Authors and Affiliations

  1. Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-Sen University, No.600 Tianhe Road, Tianhe District, Guangzhou, 510630, China

    Rongdang Fu & Xiaohong Zhang

  2. Department of Hepatic Surgery, The Affiliated Foshan Hospital of Sun Yat-Sen University, Foshan, 528000, China

    Rongdang Fu, Jieyuan Li & Huanwei Chen

  3. Department of HBP Surgery II, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China

    Shaotao Jiang

Authors
  1. Rongdang Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaotao Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jieyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huanwei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaohong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

(I) Conception and design: HC and XZ; (II) Administrative support: HC and XZ; (III) Provision of study materials: HC and XZ; (IV) Collection and assembly of data: RF, SJ, and JL; (V) Data analysis and interpretation: RF, SJ, and XZ; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Corresponding authors

Correspondence to Huanwei Chen or Xiaohong Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest in this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, R., Jiang, S., Li, J. et al. Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression. Med Oncol 37, 24 (2020). https://doi.org/10.1007/s12032-020-01350-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-020-01350-4

Keywords

Search

Navigation