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.

Opinion

Revisiting the role of ABC transporters in multidrug-resistant cancer

Abstract

Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance-associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re-evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood–brain barrier.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Structure and mechanism of three ABC transporters.
Fig. 2: Upregulation of ABCB1 via promoter capture.
Fig. 3: Expression of ABCB1 and ABCG2 in patient tumour samples.
Fig. 4: Effect of transporter deletion on plasma or brain levels of drugs.
Fig. 5: The utility and function of positron emission tomography radiotracers and other probes for imaging ABC transporter function, using the central nervous system as a model.

References

  1. 1.

    Gottesman, M. M., Lavi, O., Hall, M. D. & Gillet, J. P. Toward a better understanding of the complexity of cancer drug resistance. Annu. Rev. Pharmacol. Toxicol. 56, 85–102 (2016).

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Tamaki, A., Ierano, C., Szakacs, G., Robey, R. W. & Bates, S. E. The controversial role of ABC transporters in clinical oncology. Essays Biochem. 50, 209–232 (2011).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Sharom, F. J. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9, 105–127 (2008).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Schinkel, A. H. & Jonker, J. W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55, 3–29 (2003).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2, 48–58 (2002).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Goldstein, M. N., & Slotnick, I. J. & Journey, L. J. In vitro studies with HeLa cell line sensitive and resistant to actinomycin D. Ann. NY Acad. Sci. 89, 474–483 (1960).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Biedler, J. L. & Riehm, H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res. 30, 1174–1184 (1970).

    PubMed  CAS  Google Scholar 

  8. 8.

    Dano, K. Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim. Biophys. Acta 323, 466–483 (1973).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Juliano, R. L. & Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455, 152–162 (1976).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Gros, P., Croop, J., Roninson, I., Varshavsky, A. & Housman, D. E. Isolation and characterization of DNA sequences amplified in multidrug-resistant hamster cells. Proc. Natl Acad. Sci. USA 83, 337–341 (1986).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Roninson, I. B. et al. Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc. Natl Acad. Sci. USA 83, 4538–4542 (1986).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Ueda, K. et al. The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem. Biophys. Res. Commun. 141, 956–962 (1986).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Gros, P., Ben Neriah, Y., Croop, J. M. & Housman, D. E. Isolation and expression of a complimentary DNA that confers multidrug resistance. Nature 323, 728–731 (1986).

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Gottesman, M. M. & Ling, V. The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett. 580, 998–1009 (2006).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Cole, S. P. C. et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258, 1650–1654 (1992).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Mirski, S. E. L., Gerlach, J. H. & Cole, S. P. C. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 47, 2594–2598 (1987).

    PubMed  CAS  Google Scholar 

  17. 17.

    Doyle, L. A. et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl Acad. Sci. USA 95, 15665–15670 (1998).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V. & Dean, M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 58, 5337–5339 (1998).

    PubMed  CAS  Google Scholar 

  19. 19.

    Miyake, K. et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res. 59, 8–13 (1999).

    PubMed  CAS  Google Scholar 

  20. 20.

    Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C. & Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5, 219–234 (2006).

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Ambudkar, S. V., Kimchi-Sarfaty, C., Sauna, Z. E. & Gottesman, M. M. P-Glycoprotein: from genomics to mechanism. Oncogene 22, 7468–7485 (2003).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Dean, M., Hamon, Y. & Chimini, G. The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res. 42, 1007–1017 (2001).

    PubMed  CAS  Google Scholar 

  23. 23.

    Esser, L. et al. Structures of the multidrug transporter P-glycoprotein reveal asymmetric ATP binding and the mechanism of polyspecificity. J. Biol. Chem. 292, 446–461 (2017).

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Johnson, Z. L. & Chen, J. Structural basis of substrate recognition by the multidrug resistance protein MRP1. Cell 168, 1075–1085 e9 (2017).

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Taylor, N. M. I. et al. Structure of the human multidrug transporter ABCG2. Nature 546, 504–509 (2017).

    PubMed  CAS  Google Scholar 

  26. 26.

    Burke, M. A. & Ardehali, H. Mitochondrial ATP-binding cassette proteins. Transl Res. 150, 73–80 (2007).

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Chapuy, B. et al. Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22, 1576–1586 (2008).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Kashiwayama, Y. et al. 70-kDa peroxisomal membrane protein related protein (P70R/ABCD4) localizes to endoplasmic reticulum not peroxisomes, and NH2-terminal hydrophobic property determines the subcellular localization of ABC subfamily D proteins. Exp. Cell Res. 315, 190–205 (2009).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Tsuchida, M., Emi, Y., Kida, Y. & Sakaguchi, M. Human ABC transporter isoform B6 (ABCB6) localizes primarily in the Golgi apparatus. Biochem. Biophys. Res. Commun. 369, 369–375 (2008).

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Tarling, E. J., de Aguiar Vallim, T. Q. & Edwards, P. A. Role of ABC transporters in lipid transport and human disease. Trends Endocrinol. Metab. 24, 342–350 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Welch, E. M. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91 (2007).

    PubMed  Article  Google Scholar 

  32. 32.

    Cohen, F. E. & Kelly, J. W. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Robert, R. et al. Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol. Pharmacol. 73, 478–489 (2008).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Basseville, A. et al. Histone deacetylase inhibitors influence chemotherapy transport by modulating expression and trafficking of a common polymorphic variant of the ABCG2 efflux transporter. Cancer Res. 72, 3642–3651 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Ma, T. et al. High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. J. Biol. Chem. 277, 37235–37241 (2002).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Hillebrand, M. et al. Live cell FRET microscopy: homo- and heterodimerization of two human peroxisomal ABC transporters, the adrenoleukodystrophy protein (ALDP, ABCD1) and PMP70 (ABCD3). J. Biol. Chem. 282, 26997–27005 (2007).

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Nalepa, G., Rolfe, M. & Harper, J. W. Drug discovery in the ubiquitin-proteasome system. Nat. Rev. Drug Discov. 5, 596–613 (2006).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Grove, D. E., Rosser, M. F., Ren, H. Y., Naren, A. P. & Cyr, D. M. Mechanisms for rescue of correctable folding defects in CFTRDelta F508. Mol. Biol. Cell 20, 4059–4069 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Genin, E. C., Gondcaille, C., Trompier, D. & Savary, S. Induction of the adrenoleukodystrophy-related gene (ABCD2) by thyromimetics. J. Steroid Biochem. Mol. Biol. 116, 37–43 (2009).

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Kerem, E. Pharmacologic therapy for stop mutations: how much CFTR activity is enough? Curr. Opin. Pulm. Med. 10, 547–552 (2004).

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Ramalho, A. S. et al. Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 27, 619–627 (2002).

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Mlejnek, P., Kosztyu, P., Dolezel, P., Bates, S. E. & Ruzickova, E. Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels. Chem. Biol. Interact. 273, 171–179 (2017).

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Ween, M. P., Armstrong, M. A., Oehler, M. K. & Ricciardelli, C. The role of ABC transporters in ovarian cancer progression and chemoresistance. Crit. Rev. Oncol. Hematol. 96, 220–256 (2015).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Fletcher, J. I., Williams, R. T., Henderson, M. J., Norris, M. D. & Haber, M. ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug Resist. Updat. 26, 1–9 (2016).

    PubMed  Article  Google Scholar 

  45. 45.

    Beretta, G. L., Cassinelli, G., Pennati, M., Zuco, V. & Gatti, L. Overcoming ABC transporter-mediated multidrug resistance: the dual role of tyrosine kinase inhibitors as multitargeting agents. Eur. J. Med. Chem. 142, 271–289 (2017).

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    de Lange, E. C. Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Adv. Drug Deliv. Rev. 56, 1793–1809 (2004).

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Kannan, P. et al. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin. Pharmacol. Ther. 86, 368–377 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    Choi, Y. H. & Yu, A. M. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr. Pharm. Des. 20, 793–807 (2014).

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    U.S. Food & Drug Administration. Center for Drug Evaluation and Research (CDER) in vitro metabolism- and transporter-mediated drug-drug: interaction studies guidance for industry. FDA https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM581965.pdf (2017).

  50. 50.

    Sharom, F. J. The P-glycoprotein multidrug transporter. Essays Biochem. 50, 161–178 (2011).

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Cole, S. P. Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annu. Rev. Pharmacol. Toxicol. 54, 95–117 (2014).

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Mao, Q. & Unadkat, J. D. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport — an update. AAPS J. 17, 65–82 (2015).

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Goldstein, L. J. et al. Expression of a multidrug resistance gene in human cancers. J. Natl Cancer Inst. 81, 116–124 (1989).

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Amiri-Kordestani, L., Basseville, A., Kurdzeil, K., Fojo, A. & Bates, S. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug. Resist. Updat. 15, 50–61 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Robey, R. W., Massey, P. R., Amiri-Kordestani, L. & Bates, S. E. ABC transporters: unvalidated therapeutic targets in cancer and the CNS. Anticancer Agents Med. Chem. 10, 625–633 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Leonard, G. D., Fojo, T. & Bates, S. E. The role of ABC transporters in clinical practice. Oncologist 8, 411–424 (2003).

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Binkhathlan, Z. & Lavasanifar, A. P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. Curr. Cancer Drug Targets 13, 326–346 (2013).

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Robey, R. et al. Efflux of rhodamine from CD56+ cells as a surrogate marker for reversal of P-glycoprotein-mediated drug efflux by PSC 833. Blood 93, 306–314 (1999).

    PubMed  CAS  Google Scholar 

  59. 59.

    Witherspoon, S. M. et al. Flow cytometric assay of modulation of P-glycoprotein function in whole blood by the multidrug resistance inhibitor GG918. Clin. Cancer Res. 2, 7–12 (1996).

    PubMed  CAS  Google Scholar 

  60. 60.

    Leonard, G. D., Polgar, O. & Bates, S. E. ABC transporters and inhibitors: new targets, new agents. Curr. Opin. Investig. Drugs 3, 1652–1659 (2002).

    PubMed  CAS  Google Scholar 

  61. 61.

    de Bruin, M., Miyake, K., Litman, T., Robey, R. & Bates, S. E. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 146, 117–126 (1999).

    PubMed  Article  Google Scholar 

  62. 62.

    Minderman, H., O’Loughlin, K. L., Pendyala, L. & Baer, M. R. VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin. Cancer Res. 10, 1826–1834 (2004).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Qadir, M. et al. Cyclosporin A is a broad-spectrum multidrug resistance modulator. Clin. Cancer Res. 11, 2320–2326 (2005).

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Robey, R. W. et al. Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Res. 64, 1242–1246 (2004).

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    List, A. F. et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 98, 3212–3220 (2001).

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Cripe, L. D. et al. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood 116, 4077–4085 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67.

    Libby, E. & Hromas, R. Dismounting the MDR horse. Blood 116, 4037–4038 (2010).

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Dy, G. K. & Adjei, A. A. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J. Clin. 63, 249–279 (2013).

    PubMed  Article  Google Scholar 

  69. 69.

    Wei, X. X. et al. A phase I study of abiraterone acetate combined with BEZ235, a dual PI3K/mTOR inhibitor, in metastatic castration resistant prostate cancer. Oncologist 22, 503–e43 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Lin, J. et al. A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone for patients with metastatic castration-resistant prostate cancer progressing on abiraterone. Oncologist 21, 1296–1297e (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Dai, C. et al. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 68, 7905–7914 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Mi, Y. J. et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Res. 70, 7981–7991 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Tiwari, A. et al. Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem. Pharmacol. 78, 153–161 (2009).

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Katayama, R. et al. P-glycoprotein mediates ceritinib resistance in anaplastic lymphoma kinase-rearranged non-small cell lung cancer. EBioMedicine 3, 54–66 (2016).

    PubMed  Article  Google Scholar 

  75. 75.

    Mathias, T. J. et al. The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations. Invest. New Drugs 33, 300–309 (2015).

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Dohse, M. et al. Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab. Dispos. 38, 1371–1380 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Kerklaan, B. M. et al. Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours. Br. J. Cancer 113, 706–715 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Basseville, A. et al. in ABC Transporters — 40 Years On (ed. George, A. M.) 195–226 (Springer, Cham, 2016).

  79. 79.

    Wilson, C. S. et al. Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. Blood 108, 685–696 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Patch, A. M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Huff, L. M., Wang, Z., Iglesias, A., Fojo, T. & Lee, J. S. Aberrant transcription from an unrelated promoter can result in MDR-1 expression following drug selection in vitro and in relapsed lymphoma samples. Cancer Res. 65, 11694–11703 (2005).

    PubMed  Article  Google Scholar 

  82. 82.

    Huff, L. M., Lee, J. S., Robey, R. W. & Fojo, T. Characterization of gene rearrangements leading to activation of MDR-1. J. Biol. Chem. 281, 36501–36509 (2006).

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Gillet, J. P. et al. Clinical relevance of multidrug resistance gene expression in ovarian serous carcinoma effusions. Mol. Pharm. 8, 2080–2088 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    Marzac, C. et al. ATP binding cassette transporters associated with chemoresistance: transcriptional profiling in extreme cohorts and their prognostic impact in a cohort of 281 acute myeloid leukemia patients. Haematologica 96, 1293–1301 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Bartholomae, S. et al. Coexpression of multiple ABC-transporters is strongly associated with treatment response in childhood acute myeloid leukemia. Pediatr. Blood Cancer 63, 242–247 (2016).

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Patel, C. et al. Multidrug resistance in relapsed acute myeloid leukemia: evidence of biological heterogeneity. Cancer 119, 3076–3083 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Raaijmakers, M. et al. Breast cancer resistance protein in drug resistance of primitive CD34+38- cells in acute myeloid leukemia. Clin. Cancer Res. 11, 2436–2444 (2005).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Ho, M., Hogge, D. & Ling, V. MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia. Exp. Hematol. 36, 433–442 (2008).

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Mohelnikova-Duchonova, B. et al. Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues. Pancreas 42, 707–716 (2013).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Suwa, H. et al. Immunohistochemical localization of P-glycoprotein and expression of the multidrug resistance-1 gene in human pancreatic cancer: relevance to indicator of better prognosis. Jpn J. Cancer Res. 87, 641–649 (1996).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Namisaki, T. et al. Differential expression of drug uptake and efflux transporters in Japanese patients with hepatocellular carcinoma. Drug Metab. Dispos. 42, 2033–2040 (2014).

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Fujikura, K. et al. BSEP and MDR3: useful immunohistochemical markers to discriminate hepatocellular carcinomas from intrahepatic cholangiocarcinomas and hepatoid carcinomas. Am. J. Surg. Pathol. 40, 689–696 (2016).

    PubMed  Article  Google Scholar 

  93. 93.

    Keizer, H. G. et al. Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution, and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells. Cancer Res. 49, 2988–2993 (1989).

    PubMed  CAS  Google Scholar 

  94. 94.

    Faneyte, I. F., Kristel, P. M. & van de Vijver, M. J. Determining MDR1/P-glycoprotein expression in breast cancer. Int. J. Cancer 93, 114–122 (2001).

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Beck, W. T. et al. Methods to detect P-glycoprotein-associated multidrug resistance in patients’ tumors: consensus recommendations. Cancer Res. 56, 3010–3020 (1996).

    PubMed  CAS  Google Scholar 

  96. 96.

    Rao, V. V., Anthony, D. C. & Piwnica-Worms, D. Multidrug resistance P-glycoprotein monoclonal antibody JSB-1 crossreacts with pyruvate carboxylase. J. Histochem. Cytochem. 43, 1187–1192 (1995).

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Kim, A., Balis, F. M. & Widemann, B. C. Sorafenib and sunitinib. Oncologist 14, 800–805 (2009).

    PubMed  Article  CAS  Google Scholar 

  98. 98.

    Dulucq, S. et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 112, 2024–2027 (2008).

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Zu, B. et al. MDR1 gene polymorphisms and imatinib response in chronic myeloid leukemia: a meta-analysis. Pharmacogenomics 15, 667–677 (2014).

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Hur, E. H. et al. C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia. Leuk. Res. 32, 1601–1604 (2008).

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    Kalgutkar, A. S. et al. N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a “chemical knock-out equivalent” to assess the impact of efflux transporters on oral drug absorption in the rat. J. Pharm. Sci. 98, 4914–4927 (2009).

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Johnatty, S. E. et al. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Gynecol. Oncol. 131, 8–14 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Rottenberg, S. et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA 104, 12117–12122 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104.

    Piwnica-Worms, D. et al. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res. 53, 977–984 (1993).

    PubMed  CAS  Google Scholar 

  105. 105.

    van Leeuwen, F. W., Buckle, T., Kersbergen, A., Rottenberg, S. & Gilhuijs, K. G. Noninvasive functional imaging of P-glycoprotein-mediated doxorubicin resistance in a mouse model of hereditary breast cancer to predict response, and assign P-gp inhibitor sensitivity. Eur. J. Nucl. Med. Mol. Imaging 36, 406–412 (2009).

    PubMed  Article  Google Scholar 

  106. 106.

    Rottenberg, S. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105, 17079–17084 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Pajic, M. et al. Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer. Cancer Res. 69, 6396–6404 (2009).

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    Zander, S. A. et al. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 70, 1700–1710 (2010).

    PubMed  Article  CAS  Google Scholar 

  109. 109.

    Zander, S. A. et al. EZN-2208 (PEG-SN38) overcomes ABCG2-mediated topotecan resistance in BRCA1-deficient mouse mammary tumors. PLoS ONE 7, e45248 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Jaspers, J. E. et al. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance. Cancer Res. 75, 732–741 (2015).

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Henneman, L. et al. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc. Natl Acad. Sci. USA 112, 8409–8414 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Rottenberg, S. & Borst, P. Drug resistance in the mouse cancer clinic. Drug Resist. Updat. 15, 81–89 (2012).

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Wu, M. et al. Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice. Proc. Natl Acad. Sci. USA 106, 7022–7027 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Malingre, M. M. et al. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br. J. Cancer 84, 42–47 (2001).

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Kuppens, I. E. et al. A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients. Clin. Cancer Res. 13, 3276–3285 (2007).

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    Burger, H. & Nooter, K. Pharmacokinetic resistance to imatinib mesylate: role of the ABC drug pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the oral bioavailability of imatinib. Cell Cycle 3, 1502–1505 (2004).

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Schinkel, A. H. et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77, 491–502 (1994).

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Durmus, S., Sparidans, R. W., Wagenaar, E., Beijnen, J. H. & Schinkel, A. H. Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Mol. Pharm. 9, 3236–3245 (2012).

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Kort, A., Sparidans, R. W., Wagenaar, E., Beijnen, J. H. & Schinkel, A. H. Brain accumulation of the EML4-ALK inhibitor ceritinib is restricted by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). Pharmacol. Res 102, 200–207 (2015).

    PubMed  Article  CAS  Google Scholar 

  121. 121.

    Kort, A. et al. Brain and testis accumulation of regorafenib is restricted by breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm. Res. 32, 2205–2216 (2015).

    PubMed  Article  CAS  Google Scholar 

  122. 122.

    Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123.

    Traxl, A. et al. Breast cancer resistance protein and P-glycoprotein influence in vivo disposition of 11C-erlotinib. J. Nucl. Med. 56, 1930–1936 (2015).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Tournier, N. et al. Strategies to inhibit ABCB1- and ABCG2-mediated efflux transport of erlotinib at the blood-brain barrier: a PET study in non-human primates. J. Nucl. Med. 58, 117–122 (2016).

    PubMed  Article  CAS  Google Scholar 

  125. 125.

    Bauer, M. et al. Pilot PET study to assess the functional interplay between ABCB1 and ABCG2 at the human blood-brain barrier. Clin. Pharmacol. Ther. 100, 131–141 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

    Bankstahl, J. P. et al. Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study. Drug Metab. Dispos. 41, 754–762 (2013).

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Imai, Y. et al. C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol. Cancer Ther. 1, 611–616 (2002).

    PubMed  CAS  Google Scholar 

  128. 128.

    Morisaki, K. et al. Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother. Pharmacol. 56, 161–172 (2005).

    PubMed  Article  CAS  Google Scholar 

  129. 129.

    Lazarova, N. et al. Synthesis and evaluation of [N-methyl-11C]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function. J. Med. Chem. 51, 6034–6043 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Seneca, N. et al. Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein. J. Nucl. Med. 50, 807–813 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  131. 131.

    Kreisl, W. C. et al. P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J. Nucl. Med. 51, 559–566 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Zhang, Y. et al. ABCG2/BCRP expression modulates D-luciferin based bioluminescence imaging. Cancer Res 67, 9389–9397 (2007).

    PubMed  Article  CAS  Google Scholar 

  133. 133.

    Bakhsheshian, J., Wei, B. R., Hall, M. D., Simpson, R. M. & Gottesman, M. M. In vivo bioluminescent imaging of ATP-binding cassette transporter-mediated efflux at the blood-brain barrier. Methods Mol. Biol. 1461, 227–239 (2016).

    PubMed  Article  CAS  Google Scholar 

  134. 134.

    Agrawal, M. et al. Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clin. Cancer Res. 9, 650–656 (2003).

    PubMed  CAS  Google Scholar 

  135. 135.

    Kelly, R. J. et al. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist, tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin. Cancer Res. 17, 569–580 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    Kelly, R. J. et al. A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. Oncologist 17, 512 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Bates, S. E., Amiri-Kordestani, L. & Giaccone, G. Drug development: portals of discovery. Clin. Cancer Res. 18, 23–32 (2012).

    PubMed  Article  CAS  Google Scholar 

  138. 138.

    The PyMOL Molecular Graphics System (DeLano Scientific, Palo Alto, CA, USA).

  139. 139.

    Knutsen, T. et al. Cytogenetic and molecular characterization of random chromosomal rearrangements activating the drug resistance gene, MDR1/P-glycoprotein, in drug-selected cell lines and patients with drug refractory ALL. Genes Chromosomes Cancer 23, 44–54 (1998).

    PubMed  Article  CAS  Google Scholar 

  140. 140.

    van Asperen, J., van Tellingen, O., Tijssen, F., Schinkel, A. H. & Beijnen, J. H. Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein. Br. J. Cancer 79, 108–113 (1999).

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Marchetti, S. et al. Effect of the drug transporters ABCB1, ABCC2, and ABCG2 on the disposition and brain accumulation of the taxane analog BMS-275,183. Invest. New Drugs 32, 1083–1095 (2014).

    PubMed  Article  CAS  Google Scholar 

  142. 142.

    Choo, E. F. et al. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol. Pharm. 11, 4199–4207 (2014).

    PubMed  Article  CAS  Google Scholar 

  143. 143.

    Vaidhyanathan, S., Mittapalli, R. K., Sarkaria, J. N. & Elmquist, W. F. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug. Metab. Dispos. 42, 1292–1300 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Tang, S. C. et al. P-glycoprotein, CYP3A, and plasma carboxylesterase determine brain and blood disposition of the mTOR Inhibitor everolimus (Afinitor) in mice. Clin. Cancer Res. 20, 3133–3145 (2014).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    de Vries, N. A. et al. Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest. New Drugs 30, 443–449 (2012).

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Lagas, J. et al. Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol. Cancer Ther. 9, 319–326 (2010).

    PubMed  Article  CAS  Google Scholar 

  147. 147.

    Tang, S. C. et al. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int. J. Cancer 130, 223–233 (2012).

    PubMed  Article  CAS  Google Scholar 

  148. 148.

    Parrish, K. E. et al. Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model. J. Pharmacol. Exp. Ther. 355, 264–271 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    Durmus, S. et al. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387. Pharmacol. Res. 76, 9–16 (2013).

    PubMed  Article  CAS  Google Scholar 

  150. 150.

    Lagas, J. S. et al. Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment. Clin. Cancer Res. 15, 2344–2351 (2009).

    PubMed  Article  CAS  Google Scholar 

  151. 151.

    Poller, B. et al. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics. Drug Metab. Dispos. 39, 729–735 (2011).

    PubMed  Article  CAS  Google Scholar 

  152. 152.

    Zhou, L. et al. The effect of breast cancer resistance protein and P-glycoprotein on the brain penetration of flavopiridol, imatinib mesylate (Gleevec), prazosin, and 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid (PF-407288) in mice. Drug Metab. Dispos. 37, 946–955 (2009).

    PubMed  Article  CAS  Google Scholar 

  153. 153.

    Zhang, P. et al. ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2-Inhibitors. Int. J. Cancer 137, 2007–2018 (2015).

    PubMed  Article  CAS  Google Scholar 

  154. 154.

    Sane, R., Agarwal, S., Mittapalli, R. K. & Elmquist, W. F. Saturable active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier leads to nonlinear distribution of elacridar to the central nervous system. J. Pharmacol. Exp. Ther. 345, 111–124 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. 155.

    Lin, F. et al. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin. Cancer Res. 20, 2703–2713 (2014).

    PubMed  Article  CAS  Google Scholar 

  156. 156.

    Chuan Tang, S. et al. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int. J. Cancer 134, 1484–1494 (2014).

    Article  CAS  Google Scholar 

  157. 157.

    Durmus, S. et al. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699). Pharm. Res. 32, 37–46 (2015).

    PubMed  Article  CAS  Google Scholar 

  158. 158.

    Wang, T., Agarwal, S. & Elmquist, W. F. Brain distribution of cediranib is limited by active efflux at the blood-brain barrier. J. Pharmacol. Exp. Ther. 341, 386–395 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  159. 159.

    Polli, J. et al. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab. Dispos. 37, 439–442 (2009).

    PubMed  Article  CAS  Google Scholar 

  160. 160.

    Tang, S. C. et al. P-glycoprotein, CYP3A, and plasma carboxylesterase determine brain disposition and oral availability of the novel taxane cabazitaxel (Jevtana) in Mice. Mol. Pharm. 12, 3714–3723 (2015).

    PubMed  Article  CAS  Google Scholar 

  161. 161.

    Lin, F. et al. Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. Clin. Cancer Res. 19, 2084–2095 (2013).

    PubMed  Article  CAS  Google Scholar 

  162. 162.

    de Vries, N. A. et al. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin. Cancer Res. 13, 6440–6449 (2007).

    PubMed  Article  CAS  Google Scholar 

  163. 163.

    Salphati, L., Lee, L. B., Pang, J., Plise, E. G. & Zhang, X. Role of P-glycoprotein and breast cancer resistance protein-1 in the brain penetration and brain pharmacodynamic activity of the novel phosphatidylinositol 3-kinase inhibitor GDC-0941. Drug Metab. Dispos. 38, 1422–1426 (2010).

    PubMed  Article  CAS  Google Scholar 

  164. 164.

    Vaidhyanathan, S. et al. Factors influencing the central nervous system distribution of a novel phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor GSK2126458: implications for overcoming resistance with combination therapy for melanoma brain metastases. J. Pharmacol. Exp. Ther. 356, 251–259 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. 165.

    Marchetti, S. et al. Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA. Invest. New Drugs 31, 1125–1135 (2013).

    PubMed  Article  CAS  Google Scholar 

  166. 166.

    Mittapalli, R. K., Vaidhyanathan, S., Dudek, A. Z. & Elmquist, W. F. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J. Pharmacol. Exp. Ther. 344, 655–664 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. 167.

    Wang, J. et al. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice. Pharmacol. Res. 17, 31228–31238 (2017).

    Google Scholar 

  168. 168.

    Kort, A. et al. Brain accumulation of ponatinib and its active metabolite, N-desmethyl ponatinib, is limited by P-glycoprotein (P-GP/ABCB1) and breast cancer resistance protein (BCRP/ABCG2). Mol. Pharm. 14, 3258–3268 (2017).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors appreciate the help of S. Lusvarghi with figures and the editorial assistance of G. Leiman. This research was supported by the Intramural Research Program of the National Institutes of Health, US National Cancer Institute. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Affiliations

Authors

Contributions

R.W.R. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission. K.M.P. researched data for the article. M.D.H. and A.T.F. provided substantial contributions to discussions of the content and wrote the article. S.E.B. and M.M.G. provided substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Michael M. Gottesman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Related links

RCSB PDB: https://www.rcsb.org/

TCGA database: http://cancergenome.nih.gov

cBioPortal: www.cbioportal.org

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Robey, R.W., Pluchino, K.M., Hall, M.D. et al. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 18, 452–464 (2018). https://doi.org/10.1038/s41568-018-0005-8

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing