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.

  • Letter to the Editor
  • Published:

Ponatinib is not transported by ABCB1, ABCG2 or OCT-1 in CML cells

Leukemia volume 29, pages 1792–1794 (2015)Cite this article

Subjects

The third-generation tyrosine kinase inhibitor (TKI) ponatinib (Iclusig) was designed to target native and mutant isoforms of Bcr-Abl, including Bcr-AblT315I. It was approved for the treatment of CML patients with resistance to other TKIs. However, TKI resistance is complex. A suboptimal response to TKI therapy can be due to the development of other Bcr-Abl-dependent resistance mechanisms including reduced activity of the drug-influx transporter organic cation transporter 1 (OCT-1),1, 2, 3 or increased expression of drug-efflux denosine triphosphate (ATP)-binding cassette transporters, commonly ABCB1 and ABCG2.1, 4, 5, 6, 7, 8 We and others1, 2, 3, 9 have demonstrated that OCT-1 is an influx pump for imatinib and confirmed its central role in determining the intracellular imatinib concentration.1, 2, 3 ABCB1 and ABCG2 are reported to be efflux transporters for dasatinib and other TKIs,5, 6, 7 and the expression of these proteins has been associated with TKI resistance.1, 5, 6, 7 Recent studies have implicated ponatinib as a potent ABCG2 inhibitor, and a less potent ABCB1 inhibitor,10 however, the transport mechanism for ponatinib into target leukemic cells remained elusive. In this study, we investigated whether ABCB1, ABCG2 or OCT are involved in the transportation of ponatinib.

To assess the role of ABCG2 in ponatinib cellular efflux, IC50ponatinib was determined in K562 and its ABCG2 overexpressing variant K562-ABCG2,11 in the presence and absence of the ABCG2 inhibitors Ko143 11 and pantoprazole.12 Although an approximate twofold increase in mean IC50dasatinib was observed in K562-ABCG2 (25 nM) compared to K562 cells (9.8 nM; P<0.001, n=4; Figure 1e), there was no significant difference in the mean IC50ponatinib between K562 and K562-ABCG2 cells (IC50ponatinib 7.8 and 7.1 nM, respectively, P=0.14, n=5; Figure 1e). The inclusion of the ABCG2 inhibitor Ko413 did not significantly reduce the mean IC50ponatinib in either K562-ABCG2 (P=0.81, n=3) or K562 cells (P=0.61, n=3; Figure 1f). Similarly, the ABCG2 inhibitor pantoprazole did not significantly reduce the mean IC50ponatinib value in either K562-ABCG2 (P=0.67, n=3) or K562 cells (P=0.29, n=3; Figure 1d). Therefore, these results suggest that ponatinib is not exported from leukemic cells via ABCG2.

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
Figure 2

References

  1. Thomas J, Wang L, Clark RE, Pirmohamed M . Active transport of imatinib into and out of cells: implications for drug resistance. Blood 2004; 104: 3739–3745.

    Article  CAS  PubMed  Google Scholar 

  2. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007; 110: 4064–4072.

    Article  CAS  PubMed  Google Scholar 

  3. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 2006; 108: 697–704.

    Article  CAS  PubMed  Google Scholar 

  4. Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 2004; 104: 2940–2942.

    Article  CAS  PubMed  Google Scholar 

  5. Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G et al. Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther 2005; 4: 747–752.

    Article  CAS  PubMed  Google Scholar 

  6. Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlagel U, von Bonin M et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004; 18: 401–408.

    Article  CAS  PubMed  Google Scholar 

  7. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003; 101: 2368–2373.

    Article  CAS  PubMed  Google Scholar 

  8. Ozvegy-Laczka C, Hegedus T, Varady G, Ujhelly O, Schuetz JD, Varadi A et al. High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol Pharmacol 2004; 65: 1485–1495.

    Article  PubMed  Google Scholar 

  9. White DL, Radich J, Soverini S, Saunders VA, Frede AK, Dang P et al. Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomized to high-dose imatinib achieve better responses and have lower failure rates than those randomized to standard-dose imatinib. Haematologica 2012; 97: 907–914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sen R, Natarajan K, Bhullar J, Shukla S, Fang HB, Cai L et al. The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the MDR-associated ATP-binding cassette transporter ABCG2. Mol Cancer Ther 2012; 11: 2033–2044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hiwase DK, Saunders V, Hewett D, Frede A, Zrim S, Dang P et al. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008; 14: 3881–3888.

    Article  CAS  PubMed  Google Scholar 

  12. Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF . Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol 2001; 364: 551–557.

    Article  CAS  PubMed  Google Scholar 

  13. Tang C, Schafranek L, Watkins DB, Parker WT, Moore S, Prime JA et al. Tyrosine kinase inhibitor resistance in chronic myeloid leukemia cell lines: investigating resistance pathways. Leuk Lymphoma 2011; 52: 2139–2147.

    Article  CAS  PubMed  Google Scholar 

  14. White D, Saunders V, Lyons AB, Branford S, Grigg A, To LB et al. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. Blood 2005; 106: 2520–2526.

    Article  CAS  PubMed  Google Scholar 

  15. Wang J, Hughes TP, Kok CH, Saunders VA, Frede A, Groot-Obbink K et al. Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells. Br J Cancer 2012; 106: 1772–1778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia

    L Lu, V A Saunders, T M Leclercq, T P Hughes & D L White

  2. Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    L Lu, T M Leclercq, T P Hughes & D L White

  3. Department of Haematology, SA Pathology, Adelaide, South Australia, Australia

    T P Hughes

  4. Discipline of Paediatrics, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    D L White

Authors
  1. L Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V A Saunders
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T M Leclercq
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T P Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D L White
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D L White.

Ethics declarations

Competing interests

TPH is an Advisory Board member and has received research funding and honoraria from Novartis and Bristol-Myers Squibb (Membership on an entity’s Board of Directors or advisory committee). DLW has received research funding and honoraria from Novartis and Bristol-Myers Squibb. Although Ariad provided drug for these laboratory-based studies, they had no role in the analysis of the data or the preparation of the manuscript. The remaining 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

Lu, L., Saunders, V., Leclercq, T. et al. Ponatinib is not transported by ABCB1, ABCG2 or OCT-1 in CML cells. Leukemia 29, 1792–1794 (2015). https://doi.org/10.1038/leu.2015.35

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.35

This article is cited by

Search

Advanced search

Quick links