Skip to main content

Advertisement

SpringerLink
Log in

AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells

  • Research Article
  • Published:
Tumor Biology

Abstract

Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings.

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. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.

    Article  PubMed  Google Scholar 

  2. Renehan AG, Egger M, Saunders MP, O’Dwyer ST. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials. BMJ. 2002;324:813.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.

    Article  PubMed  Google Scholar 

  4. Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29.

    Article  CAS  PubMed  Google Scholar 

  6. Giri D, Ropiquet F, Ittmann M. Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res. 1999;5:1063–71.

    CAS  PubMed  Google Scholar 

  7. Katoh M, Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014;34:280–300.

    Article  CAS  PubMed  Google Scholar 

  8. Katoh M. FGF signaling network in the gastrointestinal tract (review). Int J Oncol. 2006;29:163–8.

    CAS  PubMed  Google Scholar 

  9. 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;18:6658–67.

    Article  CAS  PubMed  Google Scholar 

  10. 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;72:2045–56.

    Article  CAS  PubMed  Google Scholar 

  11. Xie L, Su X, Zhang L, Yin X, Tang L, Zhang X, et al. FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin Cancer Res. 2013;19:2572–83.

    Article  CAS  PubMed  Google Scholar 

  12. Chen MB, Zhang Y, Wei MX, Shen W, Wu XY, Yao C, et al. Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells. Cell Signal. 2013;25:1993–2002.

    Article  CAS  PubMed  Google Scholar 

  13. Chen MB, Wu XY, Gu JH, Guo QT, Shen WX, Lu PH. Activation of AMP-activated protein kinase contributes to doxorubicin-induced cell death and apoptosis in cultured myocardial H9c2 cells. Cell Biochem Biophys. 2011;60:311–22.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao LP, Ji C, Lu PH, Li C, Xu B, Gao H. Oxygen glucose deprivation (OGD)/re-oxygenation-induced in vitro neuronal cell death involves mitochondrial cyclophilin-D/P53 signaling axis. Neurochem Res. 2013;38:705–13.

    Article  CAS  PubMed  Google Scholar 

  15. Mathur A, Ware C, Davis L, Gazdar A, Pan BS, Lutterbach B. FGFR2 is amplified in the NCI-H716 colorectal cancer cell line and is required for growth and survival. PLoS One. 2014;9:e98515.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chen MB, Wei MX, Han JY, Wu XY, Li C, Wang J, et al. MicroRNA-451 regulates AMPK/mTORC1 signaling and fascin1 expression in HT-29 colorectal cancer. Cell Signal. 2014;26:102–9.

    Article  CAS  PubMed  Google Scholar 

  17. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene. 2006;25:6436–46.

    Article  CAS  PubMed  Google Scholar 

  18. Ekstrand AI, Jonsson M, Lindblom A, Borg A, Nilbert M. Frequent alterations of the PI3K/AKT/MTOR pathways in hereditary nonpolyposis colorectal cancer. Fam Cancer. 2010;9:125–9.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang YJ, Dai Q, Sun DF, Xiong H, Tian XQ, Gao FH, et al. mTOR signaling pathway is a target for the treatment of colorectal cancer. Ann Surg Oncol. 2009;16:2617–28.

    Article  PubMed  Google Scholar 

  20. Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I. Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci U S A. 2001;98:6074–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Westwood M, van Asselt T, Ramaekers B, Whiting P, Joore M, Armstrong N, et al. KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014;18:1–132.

    Article  Google Scholar 

  22. Arrington AK, Heinrich EL, Lee W, Duldulao M, Patel S, Sanchez J, et al. Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int J Mol Sci. 2012;13:12153–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy. Ann Surg Oncol. 2010;17:1168–76.

    Article  PubMed  Google Scholar 

  24. Fakih MM. KRAS mutation screening in colorectal cancer: from paper to practice. Clin Colorectal Cancer. 2010;9:22–30.

    Article  CAS  PubMed  Google Scholar 

  25. Byron SA, Gartside MG, Wellens CL, Mallon MA, Keenan JB, Powell MA, et al. Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. Cancer Res. 2008;68:6902–7.

    Article  CAS  PubMed  Google Scholar 

  26. Jebar AH, Hurst CD, Tomlinson DC, Johnston C, Taylor CF, Knowles MA. FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene. 2005;24:5218–25.

    Article  CAS  PubMed  Google Scholar 

  27. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.

    Article  CAS  PubMed  Google Scholar 

  28. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9:59–71.

    Article  CAS  PubMed  Google Scholar 

  29. Suhara T, Kim HS, Kirshenbaum LA, Walsh K. Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. Mol Cell Biol. 2002;22:680–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR. Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol. 2003;5:647–54.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation (No. 81101801, 81101676)

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Cancer Surgery, The First Affiliated Hospital of Bengbu Medical College, 287 Chang Huai Road, Bengbu, 233004, China

    Ting-Jing Yao, Jin-Hai Zhu, De-Feng Peng, Zhen Cui & Chao Zhang

  2. Department of Medical Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China

    Pei-hua Lu

Authors
  1. Ting-Jing Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Hai Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. De-Feng Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhen Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pei-hua Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ting-Jing Yao.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yao, TJ., Zhu, JH., Peng, DF. et al. AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells. Tumor Biol. 36, 5641–5648 (2015). https://doi.org/10.1007/s13277-015-3237-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3237-1

Keywords

Search

Navigation