Investigational New Drugs

, Volume 33, Issue 2, pp 300–309 | Cite as

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

  • Trevor J. Mathias
  • Karthika Natarajan
  • Suneet Shukla
  • Kshama A. Doshi
  • Zeba N. Singh
  • Suresh V. Ambudkar
  • Maria R. Baer


Background Crenolanib (crenolanib besylate, 4-piperidinamine, 1-[2-[5-[(3-methyl-3-oxetanyl)methoxy]-1H-benzimidazol-1-yl]-8-quinolinyl]-, monobenzenesulfonate) is a potent and specific type I inhibitor of fms-like tyrosine kinase 3 (FLT3) that targets the active kinase conformation and is effective against FLT3 with internal tandem duplication (ITD) with point mutations induced by, and conferring resistance to, type II FLT3 inhibitors in acute myeloid leukemia (AML) cells. Crenolanib is also an inhibitor of platelet-derived growth factor receptor alpha and beta and is in clinical trials in both gastrointestinal stromal tumors and gliomas. Methods We tested crenolanib interactions with the multidrug resistance-associated ATP-binding cassette proteins ABCB1 (P-glycoprotein), ABCG2 (breast cancer resistance protein) and ABCC1 (multidrug resistance-associated protein 1), which are expressed on AML cells and other cancer cells and are important components of the blood–brain barrier. Results We found that crenolanib is a substrate of ABCB1, as evidenced by approximate five-fold resistance of ABCB1-overexpressing cells to crenolanib, reversal of this resistance by the ABCB1-specific inhibitor PSC-833 and stimulation of ABCB1 ATPase activity by crenolanib. In contrast, crenolanib was not a substrate of ABCG2 or ABCC1. Additionally, it did not inhibit substrate transport by ABCB1, ABCG2 or ABCC1, at pharmacologically relevant concentrations. Finally, incubation of the FLT3-ITD AML cell lines MV4-11 and MOLM-14 with crenolanib at a pharmacologically relevant concentration of 500 nM did not induce upregulation of ABCB1 cell surface expression. Conclusions Thus ABCB1 expression confers resistance to crenolanib and likely limits crenolanib penetration of the central nervous system, but crenolanib at therapeutic concentrations should not alter cellular exposure to ABC protein substrate chemotherapy drugs.


Crenolanib ABCB1 FLT3 Platelet-derived growth factor receptor Acute myeloid leukemia Glioma 



This work was funded by a Leukemia and Lymphoma Society Translational Research Award (M.R. Baer), University of Maryland, Baltimore UMMG Cancer Research Grant #CH 649 CRF, State of Maryland Department of Health and Mental Hygiene (DHMH) under the Cigarette Restitution Fund Program (M.R. Baer), and NCI Cancer Center Support Grant P30 CA134274 (UMGCC). Drs. S. Shukla and S.V. Ambudkar were supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Zimmerman EI, Turner DC, Buaboonnam J, Hu S, Orwick S, Roberts MS, Janke LJ, Ramachandran A, Stewart CF, Inaba H, Baker SD (2013) Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia. Blood 122:3607–3615. doi: 10.1182/blood-2013-07-513044 CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M (2014) Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 123:94–100. doi: 10.1182/blood-2013-10-529313 CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Zhang W, Gao C, Konopleva M, Chen Y, Jacamo RO, Borthakur G, Cortes JE, Ravandi F, Ramachandran A, Andreeff M (2014) Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies. Clin Cancer Res 20:2363–2374. doi: 10.1158/1078-0432.CCR-13-2052 CrossRefPubMedGoogle Scholar
  4. 4.
    Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, Damon LE, Perl AE, Jeschke GR, Sugita M, Carroll M, Kogan SC, Kuriyan J, Shah NP (2014) Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci U S A 111:5319–5324. doi: 10.1073/pnas.1320661111 CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Heinrich MC, Griffith D, McKinley A, Patterson J, Presnell A, Ramachandran A, Debiec-Rychter M (2012) Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res 18:4375–4384. doi: 10.1158/1078-0432.CCR-12-0625 CrossRefPubMedGoogle Scholar
  6. 6.
    Wetmore C, Broniscer A, Turner D, Wright KD, Pai-Panandiker A, Kun LE, Ramachandran A, Onar-Thomas A, Huang J, Gajjar AJ, Baker S, Stewart CF (2014) First-in-pediatrics phase I study of crenolanib besylate (CP-868,596-26) administered during and after radiation therapy (RT) in newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent high-grade glioma (HGG). J Clin Oncol 32:5s (suppl; abstr 10064)CrossRefGoogle Scholar
  7. 7.
    Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y, Tandon A, Fomchenko EI, Oka H, Levine RL, Fujii K, Ladanyi M, Holland EC (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24:2205–2218. doi: 10.1101/gad.1972310 CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Paugh BS, Zhu X, Qu C, Endersby R, Diaz AK, Zhang J, Bax DA, Carvalho D, Reis RM, Onar-Thomas A, Broniscer A, Wetmore C, Zhang J, Jones C, Ellison DW, Baker SJ (2013) Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 73:6219–6229. doi: 10.1158/0008-5472.CAN-13-1491 CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Rebecca VW, Wood E, Fedorenko IV, Paraiso KH, Haarberg HE, Chen Y, Xiang Y, Sarnaik A, Gibney GT, Sondak VK, Koomen JM, Smalley KS (2014) Evaluating melanoma drug response and therapeutic escape with quantitative proteomics. Mol Cell Proteomics 13:1844–1854. doi: 10.1074/mcp.M113.037424 CrossRefPubMedGoogle Scholar
  10. 10.
    Rosnet O, Bühring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, Arnoulet C, Chabannon C, Kanz L, Hannum C, Birnbaum D (1996) Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 10:238–248PubMedGoogle Scholar
  11. 11.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759CrossRefPubMedGoogle Scholar
  12. 12.
    Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Döhner H, Döhner K (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100:4372–4380CrossRefPubMedGoogle Scholar
  13. 13.
    Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, Löffler H, Sauerland CM, Serve H, Büchner T, Haferlach T, Hiddemann W (2002) Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100:59–66CrossRefPubMedGoogle Scholar
  14. 14.
    Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909–1918. doi: 10.1056/NEJMoa074306 CrossRefPubMedGoogle Scholar
  15. 15.
    Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink MR, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel-Wahab O, Levine RL (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366:1079–1089. doi: 10.1056/NEJMoa1112304 CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, Naoe T (2000) Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19:624–631CrossRefPubMedGoogle Scholar
  17. 17.
    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ (2010) Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 28:4339–4345. doi: 10.1200/JCO.2010.28.9678 CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, Erba H, Stuart RK, Baccarani M, Cripe LD, Tallman MS, Meloni G, Godley LA, Langston AA, Amadori S, Lewis ID, Nagler A, Stone R, Yee K, Advani A, Douer D, Wiktor-Jedrzejczak W, Juliusson G, Litzow MR, Petersdorf S, Sanz M, Kantarjian HM, Sato T, Tremmel L, Bensen-Kennedy DM, Small D, Smith BD (2011) Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 117:3294–3301. doi: 10.1182/blood-2010-08-301796 CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, Choi WW, Lok S, Cheung AM, Eaves C, Kwong YL, Leung AY (2012) Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non-responsiveness associated with a D835 mutation. Blood 119:5133–5143. doi: 10.1182/blood-2011-06-363960 CrossRefPubMedGoogle Scholar
  20. 20.
    Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B, Karaman MW, Pratz KW, Pallares G, Chao Q, Sprankle KG, Patel HK, Levis M, Armstrong RC, James J, Bhagwat SS (2009) AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114:2984–2992. doi: 10.1182/blood-2009-05-222034 CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, Zarrinkar PP, Schadt EE, Kasarskis A, Kuriyan J, Shah NP (2012) Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485:260–263. doi: 10.1038/nature11016 CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Pauwels D, Sweron B, Cools J (2012) The N676D and G697R mutations in the kinase domain of FLT3 confer resistance to the inhibitor AC220. Haematologica 97:1773–1774. doi: 10.3324/haematol.2012.069781 CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Zirm E, Spies-Weisshart B, Heidel F, Schnetzke U, Böhmer FD, Hochhaus A, Fischer T, Scholl S (2012) Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation. Br J Haematol 157:483–492. doi: 10.1111/j.1365-2141.2012.09085.x CrossRefPubMedGoogle Scholar
  24. 24.
    Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, Salerno S, Shah NP (2013) Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood 121:3165–3171. doi: 10.1182/blood-2012-07-442871 CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Lewis NL, Lewis LD, Eder JP, Reddy NJ, Guo F, Pierce KJ, Olszanski AJ, Cohen RB (2009) Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 27:5262–5269. doi: 10.1200/JCO.2009.21.8487 CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Collins R, Kantarjian HM, Levis MJ, Perl AE, Ramachandran A, Ravandi F, Ku N, Cortes JE (2014) Clinical activity of crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory acute myeloid leukemia (AML). J Clin Oncol 32:5s (suppl; abstr 7027)CrossRefGoogle Scholar
  27. 27.
    Wang XK, Fu LW (2010) Interaction of tyrosine kinase inhibitors with the MDR- related ABC transporter proteins. Curr Drug Metab 11:618–628CrossRefPubMedGoogle Scholar
  28. 28.
    Brózik A, Hegedüs C, Erdei Z, Hegedus T, Özvegy-Laczka C, Szakács G, Sarkadi B (2011) Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance? Expert Opin Drug Metab Toxicol 7:623–642. doi: 10.1517/17425255.2011.562892 CrossRefPubMedGoogle Scholar
  29. 29.
    Shukla S, Chen ZS, Ambudkar SV (2012) Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance. Drug Resist Updat 15:70–80. doi: 10.1016/j.drup.2012.01.005 CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234CrossRefPubMedGoogle Scholar
  31. 31.
    Hunter HM, Pallis M, Seedhouse CH, Grundy M, Gray C, Russell NH (2004) The expression of P-glycoprotein in AML cells with FLT3 internal tandem duplications is associated with reduced apoptosis in response to FLT3 inhibitors. Br J Haematol 127:26–33CrossRefPubMedGoogle Scholar
  32. 32.
    Robey RW, Shukla S, Steadman K, Obrzut T, Finley EM, Ambudkar SV, Bates SE (2007) Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure. Mol Cancer Ther 6:1877–1885CrossRefPubMedGoogle Scholar
  33. 33.
    Yang JJ, Milton MN, Yu S, Liao M, Liu N, Wu JT, Gan L, Balani SK, Lee FW, Prakash S, Xia CQ (2010) P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor. Drug Metab Lett 4:201–212PubMedGoogle Scholar
  34. 34.
    Zhao XQ, Dai CL, Ohnuma S, Liang YJ, Deng W, Chen JJ, Zeng MS, Ambudkar SV, Chen ZS, Fu LW (2013) Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2. Eur J Pharm Sci 49:441–450. doi: 10.1016/j.ejps.2013.04.015 CrossRefPubMedGoogle Scholar
  35. 35.
    Lagas JS, van Waterschoot RA, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH (2010) Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther 9:319–326. doi: 10.1158/1535-7163.MCT-09-0663 CrossRefPubMedGoogle Scholar
  36. 36.
    Agarwal S, Sane R, Ohlfest JR, Elmquist WF (2011) The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther 336:223–233. doi: 10.1124/jpet.110.175034 CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Hu S, Chen Z, Franke R, Orwick S, Zhao M, Rudek MA, Sparreboom A, Baker SD (2009) Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. Clin Cancer Res 15:6062–6069. doi: 10.1158/1078-0432.CCR-09-0048 CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Shukla S, Robey RW, Bates SE, Ambudkar SV (2009) Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos 37:359–365. doi: 10.1124/dmd.108.024612 CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Bhullar J, Natarajan K, Shukla S, Mathias TJ, Sadowska M, Ambudkar SV, Baer MR (2013) The FLT3 inhibitor quizartinib inhibits ABCG2 at pharmacologically relevant concentrations, with implications for both chemosensitization and adverse drug interactions. PLoS One 8:e71266. doi: 10.1371/journal.pone.0071266 CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Sen R, Natarajan K, Bhullar J, Shukla S, Fang HB, Cai L, Chen ZS, Ambudkar SV, Baer MR (2012) The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the MDR-associated ATP-binding cassette transporter ABCG2. Mol Cancer Ther 11:2033–2044. doi: 10.1158/1535-7163.MCT-12-0302 CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Shen S, Zhang W (2010) ABC transporters and drug efflux at the blood–brain barrier. Rev Neurosci 21:29–53CrossRefPubMedGoogle Scholar
  42. 42.
    Ogretmen B, Safa AR (2000) Identification and characterization of the MDR1 promoter-enhancing factor 1 (MEF1) in the multidrug resistant HL60/VCR human acute myeloid leukemia cell line. Biochemistry 39:194–204CrossRefPubMedGoogle Scholar
  43. 43.
    Marsh W, Sicheri D, Center MS (1986) Isolation and characterization of adriamycin-resistant HL-60 cells which are not defective in the initial intracellular accumulation of drug. Cancer Res 46:4053–4057PubMedGoogle Scholar
  44. 44.
    Hazlehurst LA, Foley NE, Gleason-Guzman MC, Hacker MP, Cress AE, Greenberger LW, De Jong MC, Dalton WS (1999) Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Res 59:1021–1028PubMedGoogle Scholar
  45. 45.
    Suvannasankha A, Minderman H, O’Loughlin KL, Nakanishi T, Greco WR, Ross DD, Baer MR (2004) Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function. Leukemia 18:1252–1257CrossRefPubMedGoogle Scholar
  46. 46.
    Hafkemeyer P, Licht T, Pastan I, Gottesman MM (2000) Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers. Hum Gene Ther 11:555–565CrossRefPubMedGoogle Scholar
  47. 47.
    Yanase K, Tsukahara S, Asada S, Ishikawa E, Imai Y, Sugimoto Y (2004) Gefitinib reverses breast cancer resistance protein-mediated drug resistance. Mol Cancer Ther 3:1119–1125PubMedGoogle Scholar
  48. 48.
    Quentmeier H, Reinhardt J, Zaborski M, Drexler HG (2003) FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 17:120–124CrossRefPubMedGoogle Scholar
  49. 49.
    Ambudkar SV (1998) Drug-stimulatable ATPase activity in crude membranes of humanMDR1-transfected mammalian cells. Methods Enzymol 292:504–514CrossRefPubMedGoogle Scholar
  50. 50.
    Young IT (1977) Proof without prejudice: use of the Kolmogorov-Smirnov test for the analysis of histograms from flow systems and other sources. J Histochem Cytochem 25:935–941CrossRefPubMedGoogle Scholar
  51. 51.
    Minderman H, Suvannasankha A, O’Loughlin KL, Scheffer GL, Scheper RJ, Robey RW, Baer MR (2002) Flow cytometric analysis of breast cancer resistance protein expression and function. Cytometry 48:59–65CrossRefPubMedGoogle Scholar
  52. 52.
    Sauna ZE, Ambudkar SV (2000) Evidence for a requirement for ATP hydrolysis at two distinct steps during a single turnover of the catalytic cycle of human P-glycoprotein. Proc Natl Acad Sci U S A 97:2515–2520CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Ansbro MR, Shukla S, Ambudkar SV, Yuspa SH, Li L (2013) Screening compounds with a novel high-throughput ABCB1-mediated efflux assay identifies drugs with known therapeutic targets at risk for multidrug resistance interference. PLoS One 8:e60334. doi: 10.1371/journal.pone.0060334 CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398CrossRefPubMedGoogle Scholar
  55. 55.
    Shaffer BC, Gillet JP, Patel C, Baer MR, Bates SE, Gottesman MM (2012) Drug resistance: still a daunting challenge to the successful treatment of AML. Drug Resist Updat 15:62–69. doi: 10.1016/j.drup.2012.02.001 CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Marzac C, Teyssandier I, Calendini O, Perrot JY, Faussat AM, Tang R, Casadevall N, Marie JP, Legrand O (2006) Flt3 internal tandem duplication and P-glycoprotein functionality in 171 patients with acute myeloid leukemia. Clin Cancer Res 12:7018–7024CrossRefPubMedGoogle Scholar
  57. 57.
    Plaat BE, Hollema H, Molenaar WM, Torn Broers GH, Pijpe J, Mastik MF, Hoekstra HJ, van den Berg E, Scheper RJ, van der Graaf WT (2000) Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 18:3211–3220PubMedGoogle Scholar
  58. 58.
    Théou N, Gil S, Devocelle A, Julié C, Lavergne-Slove A, Beauchet A, Callard P, Farinotti R, Le Cesne A, Lemoine A, Faivre-Bonhomme L, Emile JF (2005) Multidrug resistance proteins in gastrointestinal stromal tumors: site-dependent expression and initial response to imatinib. Clin Cancer Res 11:7593–7598CrossRefPubMedGoogle Scholar
  59. 59.
    von Bossanyi P, Diete S, Dietzmann K, Warich-Kirches M, Kirches E (1997) Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy. Acta Neuropathol (Berlin) 94:605–611CrossRefGoogle Scholar
  60. 60.
    Fruehauf JP, Brem H, Brem S, Sloan A, Barger G, Huang W, Parker R (2006) In vitro drug response and molecular markers associated with drug resistance in malignant gliomas. Clin Cancer Res 12:4523–4532CrossRefPubMedGoogle Scholar
  61. 61.
    Hu XF, Slater A, Wall DM, Parkin JD, Kantharidis P, Zalcberg JR (1996) Cyclosporin A and PSC 833 prevent up-regulation of MDR1 expression by anthracyclines in a human multidrug-resistant cell line. Clin Cancer Res 2:713–720PubMedGoogle Scholar
  62. 62.
    Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, Thiede C, Frattini M, Nybakken GE, Pratz K, Karp J, Smith BD, Levis M (2012) Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood 120:4205–4214. doi: 10.1182/blood-2012-01-402545 CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Elmeliegy MA, Bai F, Juel S, Throm S, Ramachandran A, Stewart CF (2011) Microdialysis for evaluation of crenolanib penetration in spontaneous glioblastoma murine model using a sensitive liquid chromatography mass spectrometry (LC-MS/MS) method. Proc Am Assoc Cancer Res abstract 5474Google Scholar
  64. 64.
    Tachibana T, Kato M, Takano J, Sugiyama Y (2010) Predicting drug-druginteractions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. Curr Drug Metab 11:762–777CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Trevor J. Mathias
    • 1
  • Karthika Natarajan
    • 1
    • 2
  • Suneet Shukla
    • 3
  • Kshama A. Doshi
    • 1
  • Zeba N. Singh
    • 4
  • Suresh V. Ambudkar
    • 3
  • Maria R. Baer
    • 1
    • 2
  1. 1.University of Maryland Greenebaum Cancer CenterBaltimoreUSA
  2. 2.Department of MedicineUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Laboratory of Cell Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  4. 4.Department of PathologyUniversity of Maryland School of MedicineBaltimoreUSA

Personalised recommendations