Mechanisms of resistance to FLT3 inhibitors

Drug Resistance Updates

Volumn 12, Issue 1-2, 2009, Pages 8-16

  Chu, S Haihua ^a   Small, Donald ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AC220; AML; CEP701; Combination therapy; KW 2449; Leukemic stem cells; MLN518; Multitargeted agents; NF B inhibition; PKC412; SU 5416; SU11248

Indexed keywords

5 (4 BROMO 2 CHLOROANILINO) 4 FLUORO 1 METHYL 1H BENZIMIDAZOLE 6 CARBOHYDROXAMIC ACID 2 HYDROXYETHYL ESTER; 5 [(5 FLUORO 1,2 DIHYDRO 2 OXO 3H INDOL 3 YLIDENE)METHYL] N (2 HYDROXY 3 MORPHOLINOPROPYL) 2,4 DIMETHYL 1H PYRROLE 3 CARBOXAMIDE; AC 220; CD135 ANTIGEN; CYTARABINE; DAUNORUBICIN; IMATINIB; KW 2449; LESTAURTINIB; MIDOSTAURIN; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY IMC EB10; MONOCLONAL ANTIBODY IMC NC7; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; SEMAXANIB; SORAFENIB; SUNITINIB; TANDUTINIB; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ARTICLE; CANCER RESISTANCE; CANCER SURVIVAL; CARCINOGENICITY; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; DRUG EFFICACY; DRUG MECHANISM; GENE MUTATION; HUMAN; LEUKEMOGENESIS; NONHUMAN; PRIORITY JOURNAL;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CELL PROLIFERATION; CELL SURVIVAL; DRUG RESISTANCE, NEOPLASM; FMS-LIKE TYROSINE KINASE 3; GENE EXPRESSION REGULATION, LEUKEMIC; HUMANS; LEUKEMIA, MYELOID, ACUTE; NEOPLASTIC STEM CELLS; PROTEIN KINASE INHIBITORS;

EID: 62949093541     PISSN: 13687646     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.drup.2008.12.001     Document Type: Article

References (119)

1. Abu-Duhier F.M., Goodeve A.C., Wilson G.A., Care R.S., Peake I.R., and Reilly J.T. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br. J. Haematol. 113 (2001) 983-988
2. Adnane L., Trail P.A., Taylor I., and Wilhelm S.M. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol. 407 (2005) 597-612
3. Agaram N.P., Wong G.C., Guo T., Maki R.G., Singer S., Dematteo R.P., et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47 (2008) 853-859
4. Agarwal A., Eide C.A., Harlow A., Corbin A.S., Mauro M.J., et al. An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia (2008) 10.1038/leu.2008.124
5. Barginear M.F., van Poznak C., Rosen N., Modi S., Hudis C.A., and Budman D.R. The heat shock protein 90 chaperone complex: an evolving therapeutic target. Curr. Cancer Drug Targets 8 (2008) 522-532
6. Birkenkamp K.U., Geugien M., Schepers H., Westra J., Lemmink H.H., and Vellenga E. Constitutive NF-kappaB DNA-binding activity in AML is frequently mediated by a Ras/PI3-K/PKB dependent pathway. Leukemia 18 (2004) 103-112
7. Branford S., Rudzki Z., Walsh S., Grigg A., Arthur C., Taylor K., et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 99 (2002) 3472-3475
8. Branford S., Rudzki Z., Walsh S., Parkinson I., Grigg A., Szer J., et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate binding loop (P-loop) are associated with a poor prognosis. Blood 102 (2003) 276-283
9. Broxterman H.J., and Georgopapadakou N.H. Anticancer therapeutics: addictive targets, multi-targeted drugs, new drug combinations. Drug Resist. Updates 8 (2005) 183-197
10. Burchert A. Roots of imatinib resistance: a question of self-renewal?. Drug Resist. Updates 10 (2007) 152-161
11. Carow C.E., Levenstein M., Kaufmann S.H., et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 87 (1996) 1089-1096
12. Choudhary C., Muller-Tidow C., Berdel W.E., and Serve H. Signal transduction of oncogenic Flt3. Int. J. Hematol. 82 (2005) 93-99
13. Cloos J., Goemans B.F., Hess C.J., et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 20 (2006) 1217-1220
14. Cools J., Maertens C., and Marynen P. Resistance to tyrosine kinase inhibitors: calling on extra forces. Drug Resist. Updates 8 (2005) 119-129
15. Cools J., Mentens N., Furet P., et al. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res. 64 (2004) 6385-6389
16. Corbin A.S., Stoffregen E.P., Druker B.J., and Deininger M.W. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood 101 (2003) 4611-4614
17. Cortes J., Devetten M., et al. Human pharmacokinetics of AC220, a potent and selective class III receptor tyrosine kinase inhibitor. Blood 110 (2007) 477a
18. Cortes J., Kantarjian H., et al. A phase I dose escalation study of KW-2449, an oral multi-kinase inhibitor against FLT3, Abl, FGFR1 and aurora in patients with relapsed/refractory AML, treatment resistant/intolerant CML, ALL and MDS. Blood 110 (2007) 277a
19. Deangelo D., Kovacsovics T.J., et al. Phase 1/2 study of tandutinib (MLN518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia (AML). Blood (2006) 108
20. DeAngelo D.J., Heaney M.L., et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelo-dysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 108 (2006) 50a Abstract 158
21. Dierks C., Guo G.R., Zirlik K., Stegert M.R., Manley P., Trussell C., et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14 (2008) 238-249
22. Donato N.J., Stapley J., Gallick G., Lin H., Arlinghaus E., et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101 (2003) 690-698
23. Druker B.J., O'Brien S.G., Gathmann I., Kantarjian H., Gattermann N., et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. New Engl. J. Med. 355 (2006) 2408-2417
24. Druker B.J., Sawyers C.L., Kantarjian H., Resta D.J., Reese S.F., Ford J.M., Capdeville R., and Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with Philadelphia chromosome. New Engl. J. Med. 344 (2001) 1038-1042
25. Druker B.J., Talpaz M., Resta D.J., Peng B., Buchdunger E., Ford J.M., et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New Engl. J. Med. 344 (2001) 1031-1037
26. Fiedler W., Tinnefeld H., et al. A phase II clinical study of SU-5416 in patients with refractory acute myeloid leukemia. Blood 102 (2003) 2763-2767
27. Fiedler W., Dohner H., et al. A phase I study of SU-11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105 (2005) 986-993
28. Fojo T. Multiple paths to a drug resistance phenotype: mutations, translocations, deletions and amplification of coding genes or promoter regions, epigenetic changes and microRNAs. Drug Resist. Updates 10 (2007) 59-67
29. Frelin C., Imbert V., Griessinger M., Peyron A., Rochet N., Philip P., et al. Targeting NF-kappaB activation via pharmacological inhibition of IKK2, induced apoptosis of human acute myeloid leukemia cells. Blood 105 (2005) 804-811
30. Frohling S., Schlenk R.F., Breitruck J., et al. 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 (2002) 4372-4380
31. Galimberti S., Rossi A., Palumbo G.A., Morabito F., Guerrini F., Vincelli I., et al. FLT3 mutations do not influence MDR-1 gene expression in acute myeloid leukemia. Anticancer Res. 23 (2003) 3419-3426
32. George P., Bali P., Cohen P., Tao J., Guo F., Sigua C., et al. Co-treatment with 17-allylamino-demethoxy geldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res. 64 (2004) 3645-3652
33. Giles F.J., Silverman L.R., et al. SU-5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 102 (2003) 795-801
34. Gilliland D.G., and Griffin J.D. The roles of FLT3 in hematopoiesis and leukemias. Blood 100 (2002) 1532-1542
35. Gorre M.E., Mohammed M., Ellwood K., Hsu N., Paquette R., Rao P.N., and Sawyers C.L. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293 (2001) 876-880
36. Gotze K.S., Ramirez M., Tabor K., Small D., Matthews W., and Civin C.I. FLT3high and FLT3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct. Blood 91 (1998) 1947-1958
37. Griessinger E., Frelin C., Cuburu N., et al. Preclinical targeting of NF-kappaB and FLT3 pathways in AML cells. Leukemia 22 (2008) 1466-1469
38. Griessinger E., Imbert V., Lagadec P., Gonthier N., Dubreuil P., Romanelli A., et al. AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells. Leukemia 21 (2007) 877-885
39. Griffith J., Black J., Faerman C., Swenson L., Wynn M., Lu F., et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cells 13 (2004) 169-178
40. Grundler R., Thiede C., Miething C., Steudel C., Peschel C., and Duyster J. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood 102 (2003) 646-651
41. Guzman M.L., Rossi R.M., Neelakantan S., et al. An orally available parthenolide analog selectively eradicates acute myelogenous leukemic stem and progenitor cells. Blood 110 (2007) 4427-4435
42. Guzman M.L., and Jordan C.T. Considerations for targeting malignant stem cells in leukemia. Cancer Control 11 (2004) 97-104
43. Heidel F., Solem F.K., Breitenbuecher F., et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 107 (2006) 293-300
44. Hochhaus A., Corbin A.S., La Rosee P., Muller M.C., Lahaye T., Hanfstein B., et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16 (2002) 2190-2196
45. Hu Y., Chen Y., Douglas L., and Li S. Beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukaemia. Leukemia (2008) 10.1038/leu.2008.262
46. Jiang B.H., and Liu L.Z. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist. Updates 11 (2008) 63-76
47. Jordan C.T., and Guzman M.L. Mechanisms controlling pathogenesis and survival of leukemic stem cells. Oncogene 23 (2004) 7178-7187
48. Kajiguchi T., Chung E.J., Lee S., Stine A., Kiyoi H., Naoe T., et al. FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia 21 (2007) 2476-2484
49. Kancha R.K., Miething C., Peschel C., Götze K.S., and Duyster J. Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation. Haematologica 93 (2008) 1718-1722
50. Kavalerchik E., Goff D., and Jamieson C.H. Chronic myeloid leukemia stem cells. J. Clin. Oncol. 26 (2008) 2911-2915
51. Kelly L.M., Kutok J.L., Williams I.R., Boulton C.L., Amaral S.M., Curley D.P., et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc. Natl. Acad. Sci. (U.S.A.) 99 (2002) 8283-8288
52. Kelly L.M., Liu Q., Kutok J.L., Williams I.R., Boulton C.L., and Gilliland D.G. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 99 (2002) 310-318
53. Kim H., Kojima K., Swindle C.S., Cotta C.V., Huo Y., Reddy V., and Klug C.A. FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia. Blood 111 (2008) 1567-1574
54. Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br. J. Haematol. 138 (2007) 687-699
55. Knapper S., Burnett A.K., Littlewood T., et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 108 (2006) 3262-3270
56. Knapper S., Mills K.I., Gilkes A.F., Austin S.J., Walsh V., and Burnett A.K. The effects of lestaurtinib (CEP701) and PKC412 on primary AML blasts: the induction of cytotoxicity varies with dependence on FLT3 signaling in both FLT3-mutated and wild-type cases. Blood 108 (2006) 3494-3503
57. Kohl T.M., Hellinger C., Ahmed F., Buske C., Hiddemann W., Bohlander S.K., and Spiekermann K. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia 21 (2007) 1763-1772
58. Krause D.S., and van etten R.A. Right on target: eradicating leukemic stem cells. Trends Mol. Med. 13 (2007) 470-481
59. Levis M., Brown P., Smith B.D., Stine A., Pham R., Stone R., et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 108 (2006) 3477-3483
60. Levis M., Pham R., Smith B.D., and Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 104 (2004) 1145-1150
61. Levis M., and Small D. FLT3: ITDoes matter in leukemia. Leukemia 17 (2003) 1738-1752
62. Levis M., Murphy K.M., Pham R., Kim K.T., Stine A., Li L., et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 106 (2005) 673-680
63. Levis M., Smith B.D., Beran M., Baer M.R., Erba H.P., Cripe L., et al. A randomized, open-label study of lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition. Blood 106 (2005) 403a
64. Levis M., Stine A., Rosalyn Pham B., Karp J., Stone R., Estey E., et al. Pharmacokinetic and pharmacodynamic studies of lestaurtinib (CEP-701) and PKC-412: cytotoxicity is often dependent on non-FLT3 mediated effects. Blood 106 (2005) (Abstract #2463)
65. Miething C., Mugler C., Brero S., Hoepfl J., Geigl J., Speicher M.R., et al. Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment. Proc. Natl. Acad. Sci. (U.S.A.) 104 (2007) 4594-4599
66. Mohi M.G., Boulton C., Gu T.L., et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl. Acad. Sci. (U.S.A.) 101 (2004) 3130-3135
67. Möllgård L., Deneberg S., Nahi H., Bengtzen S., Jonsson-Videsater K., Fioretos T., et al. The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia. Cancer Chem. Pharmacol. 62 (2008) 439-448
68. Nakao M., Iwai T., et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10 (1996) 1911-1918
69. Nishioka C., Ikezoe T., Yang J., Takeshita A., Taniguchi A., Komatscu N., et al. Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene. Leuk. Res. 32 (2008) 865-872
70. O'Farrell A.M., Foran J.M., Fiedler W., et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin. Cancer Res. 9 (2003) 5465-5476
71. Odgerel T., Wada T., Shimizu R., Futaki K., Kano Y., and Furukawa Y. The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations. Oncogene 27 (2008) 3102-3110
72. Patyna S., Mendel D.B., O'Farrell A.M., Liang C., Guan H., Vojkovsky T., et al. SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol. Cancer Ther. 5 (2006) 1774-1782
73. Piloto O., Wright M., Brown P., Kim K.T., Levis M., and Small D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 109 (2007) 1643-1652
74. Pocaly M., Etienne G., Dupouy M., Lapaillerie D., Claverol S., Vilain S., et al. Proteomic analysis of an imatinib-resistant K562 cell line highlights opposing roles of heat shock cognate 70 and heat shock 70 proteins in resistance. Proteomics 8 (2008) 2394-2406
75. Pratz K.W., Cortes J., Roboz G.J., et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood (2009) 10.1182/blood-2008-09-177030
76. Quintás-Cardama A., Andreeff M., et al. Phase I trial of intermittent administration of sorafenib (BAY 43-9006) for patients with refractory/relapsed acute myelogenous leukemia. J. Clin. Oncol. 25 (2007) 7018 (Abstract)
77. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukemia. Nat. Rev. Cancer 5 (2005) 172-183
78. Roche-Lestienne C., Soenen-Cornu V., Grardel-Duflos N., Lai J.L., Philippe N., Facon T., et al. Several types of mutations of the ABl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100 (2002) 1014-1018
79. Schaich M., Soucek S., Thiede C., Ehninger G., Illmer T., et al. MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br. J. Haematol. 128 (2005) 324-332
80. Scholl S., Bleul A., Spies-Weisshart B., Kunert C., Höffken K., and von Eggeling F. Specific pattern of protein expression in acute myeloid leukemia harboring FLT3-ITD mutations. Leukemia 48 (2007) 2418-2423
81. Sengupta A., Chandra S., Banerji S.K., Ghosh R., Roy R., and Banerjee S. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. Leukemia 21 (2007) 949-955
82. Shah N.P., Nicoll J.M., Nagar B., Gorre M.E., Paquette R.L., Kuriyan J., and Sawyers C.L. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cells 2 (2002) 117-125
83. Shankar D.B., Tapang P., Owen McCall J., et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. Blood 109 (2007) 3400-3408
84. Sherbenou D.W., Humayun A., McGreevey L.S., Harrell P., Yang R., Mauro M., et al. Mutations of the BCR-ABL-kinase domain occur in a minority of patients with stable complete cytogenetic response to imatinib. Leukemia 21 (2007) 489-493
85. Shih L.Y., Huag C.F., Wang P.N., et al. Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 18 (2004) 466-475
86. Shih L.Y., Huang C.F., Wu J.H., et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 100 (2002) 2387-2392
87. Siendones E., Barbarroja N., Torres L.A., Buendia P., Velasco F., Dorado G., et al. Inhibition of Flt3-activating mutations does not prevent constitutive activation of ERK/Akt/STAT pathways in some AML cases: a possible cause for the limited effectiveness of monotherapy with small-molecule inhibitors. Hematol. Oncol. 25 (2007) 30-37
88. Small D. FLT3 mutations: biology of treatment. Hematol. Am. Soc. Hematol. Educ. Prog. (2006) 178-184
89. Smith B.D., Levis M., Beran M., et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 103 (2004) 3669-3676
90. Sohal J., Phan V.T., Chan P.V., Davis E.M., Patel B., Kelly L.M., et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood 101 (2003) 3188-3197
91. Stone R., Paquette R.L., et al. Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine induction and high-dose cytarabine consolidation in newly diagnosed patients with AML. Blood 106 (2005) 121a
92. Stone R.M., Klimek V., DeAngelo D.J., et al. PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial. Blood 100 (2002) 86A
93. Stubbs M.C., and Armstrong S.A. Therapeutic implications of leukemia stem cell development. Clin. Cancer Res. 13 (2007) 3439-3442
94. Takahashi S., Harigae H., Ishii K.K., Inomata M., Fujiwara T., Yokoyama H., et al. Over-expression of Flt3 induces NF-kappaB pathway and increases the expression of IL-6. Leuk. Res. 29 (2005) 893-899
95. Tam W.F., and Gilliland D.G. Can FLT3 inhibitors overcome resistance in AML?. Best Pract. Res. Clin. Haematol. 21 (2008) 13-20
96. Thiede C., Steudel C., Mohr B., et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and "f" identification of subgroups with poor prognosis. Blood 99 (2002) 4326-4335
97. Tickenbrock L., Berdel W.E., and Serve H. Emerging Flt3 kinase inhibitors in the treatment of leukaemia. Expert Opin. Emerg. Drugs 11 (2006) 153-165
98. Tickenbrock L., Schwable J., Wiedehage M., Steffen B., Sargin B., Choudhary C., et al. Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood 105 (2005) 3699-3706
99. Tortora G., Bianco R., Daniele G., et al. Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumors and haematologic malignancies. Drug Resist. Updates 10 (2007) 81-100
100. Van Rhenen A., van Dongen A., Kelder A., et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 110 (2007) 2659-2666
101. Wadleigh M., DeAngelo D.J., Griffin J.D., and Stone R.M. After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies. Blood 105 (2005) 22-30
102. Wang L., Wang J., Blaser B., Duchemin A., Kusewitt D., Liu T., et al. Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia. Blood 110 (2007) 2075-2083
103. Wang Y., Brendel C., Barett C., Erben P., Manley P.W., et al. Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood 109 (2007) 2147-2155
104. Wei Y., Olsson B., Hezaveh R., Ricksten A., Stockelberg D., and Wadenvik H. Not all imatinib resistance in CML are BCR-ABL kinase domain mutations. Ann. Hematol. 85 (2006) 841-847
105. Weisberg E., Boulton C., Kelly L.M., et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cells 1 (2002) 433-443
106. Weisberg E., Kung A.L., Wright R., Moreno D., Catley L., Ray A., et al. Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells. Mol. Cancer Ther. 6 (2007) 1951-1961
107. Weisberg E., Roesel J., Bold G., et al. Anti-leukemic effects of the novel, mutant FLT3 inhibitor, NVP-AST487: effects of PKC412-sensitive and -resistant FLT3-expressing cells. Blood 112 (2008) 5161-5170
108. Wilhelm S.M., Tang L., et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64 (2004) 7099-7109
109. Wu J., Kong L.Y., Peng Z., Ying Y., Bornmann W.G., Darnay B.G., et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J. Natl. Cancer Inst. 100 (2008) 926-939
110. Yamamoto Y., Kiyoi H., Nakano Y., et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97 (2001) 2434-2439
111. Yee K.W., O'Farrell A.M., Smolich B.D., Cherrington J.M., McMahon G., Wait C.L., et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 100 (2002) 2941-2949
112. Zhang L., Ming L., and Yu J. BH3 mimetics to improve cancer therapy; mechanisms and examples. Drug Resist. Updates 10 (2007) 207-217
113. Zhang W., Shi Y.X., McQueen T., Harris D., Ling X., Estrov Z., et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J. Natl. Cancer Inst. 100 (2008) 184-198
114. Zhao M., Kiyoi H., Yamamoto Y., Ito M., Towatari M., Omura S., et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 14 (2000) 374-378
115. Zheng R., Levis M., Li L., Weir E.G., and Small D. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression. Blood 103 (2004) 1883-1890
116. Zheng R., Piloto O., et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 103 (2004) 267-274
117. Zheng R. Mutant FLT3 signaling contributes to a block in myeloid differentiation. Leuk. Lymphoma 46 (2005) 1679-1687
118. Zhou J., Jasinghe V.J., Bi C., Neo C.H., Pan M., Poon L.F., et al. In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor. Leuk. Res. 32 (2008) 1091-1100
119. Zhou J., Pan M., Xie Z., Loh S.L., Bi C., Tai Y.C., et al. Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle-regulated genes and c-Mos-mediated MAPK pathway. Leukemia 22 (2008) 138-146