Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How?

Solène Fernandez, Vanessa Desplat, Arnaud Villacreces, Amélie V Guitart, Noël Milpied, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet, Pierre-Yves Dumas, Solène Fernandez, Vanessa Desplat, Arnaud Villacreces, Amélie V Guitart, Noël Milpied, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet, Pierre-Yves Dumas

Abstract

Acute myeloid leukemia (AML) is a myeloid malignancy carrying a heterogeneous molecular panel of mutations participating in the blockade of differentiation and the increased proliferation of myeloid hematopoietic stem and progenitor cells. The historical "3 + 7" treatment (cytarabine and daunorubicin) is currently challenged by new therapeutic strategies, including drugs depending on the molecular landscape of AML. This panel of mutations makes it possible to combine some of these new treatments with conventional chemotherapy. For example, the FLT3 receptor is overexpressed or mutated in 80% or 30% of AML, respectively. Such anomalies have led to the development of targeted therapies using tyrosine kinase inhibitors (TKIs). In this review, we document the history of TKI targeting, FLT3 and several other tyrosine kinases involved in dysregulated signaling pathways.

Keywords: acute myeloid leukemia; inhibitors; targeted therapy; tyrosine kinase.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Signaling in AML FLT3-ITD. Like most receptor tyrosine kinases, FLT3 is activated following ligand-induced dimerization and then signals through two major pathways: PI3-kinase/AKT and RAS/RAF/MAP-kinases. Internal tandem duplication by changing structure and localization induces constitutive activation of FLT3 signaling pathway with a large increase in STAT5 activation.
Figure 2
Figure 2
Tyrosine kinase inhibitors in FLT3-ITD AML. Midostaurin and gilteritinib are shown in bold as the only two FDA-approved TKIs. All the others are under development and most are being tested in clinical trials. Those still in preclinical development are not presented.

References

    1. Robinson D.R., Wu Y.M., Lin S.F. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548–5557. doi: 10.1038/sj.onc.1203957.
    1. Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–1934. doi: 10.1126/science.1075762.
    1. Wang H., Chevalier D., Larue C., Ki Cho S., Walker J.C. The protein phosphatases and protein kinases of Arabidopsis thaliana. Arabidopsis Book. 2007;5:e0106.
    1. Eckhart W., Hutchinson M., Hunter T. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell. 1979;18:925–933. doi: 10.1016/0092-8674(79)90205-8.
    1. Weiss A., Schlessinger J. Switching signals on or off by receptor dimerization. Cell. 1998;94:277–280. doi: 10.1016/S0092-8674(00)81469-5.
    1. Duong-Ly K.C., Peterson J.R. The human kinome and kinase inhibition. Curr. Prot. Pharmacol. 2013;60:2–9.
    1. Traxler P.M., Furet P., Mett H., Buchdunger E., Meyer T., Lydon N. 4-(Phenylamino)pyrrolopyrimidines: Potent and selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem. 1996;39:2285–2292. doi: 10.1021/jm960118j.
    1. Carroll M. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90:4947–4952.
    1. Fleuren E.D., Zhang L., Wu J., Daly R.J. The kinome ‘at large’ in cancer. Nat. Rev. Cancer. 2016;16:83–98. doi: 10.1038/nrc.2015.18.
    1. Gross S., Rahal R., Stransky N., Lengauer C., Hoeflich K.P. Targeting cancer with kinase inhibitors. J. Clin. Invest. 2015;125:1780–1789. doi: 10.1172/JCI76094.
    1. Roskoski R. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 2016;103:26–48. doi: 10.1016/j.phrs.2015.10.021.
    1. Bhullar K.S., Lagaron N.O., McGowan E.M., Parmar I., Jha A., Hubbard B.P., Rupasinghe H.P.V. Kinase-targeted cancer therapies: Progress, challenges and future directions. Mol. Cancer. 2018;17:48. doi: 10.1186/s12943-018-0804-2.
    1. Paulson R.F., Bernstein A. Receptor tyrosine kinases and the regulation of hematopoiesis. Semin. Immunol. 1995;7:267–277. doi: 10.1006/smim.1995.0031.
    1. Rohrschneider L.R., Bourette R.P., Lioubin M.N., Algate P.A., Myles G.M., Carlberg K. Growth and differentiation signals regulated by the M-CSF receptor. Mol. Reprod. Dev. 1997;46:96–103. doi: 10.1002/(SICI)1098-2795(199701)46:1<96::AID-MRD15>;2-1.
    1. Bernstein A., Forrester L., Reith A.D., Dubreuil P., Rottapel R. The murine W/c-kit and Steel loci and the control of hematopoiesis. Semin. Hematol. 1991;28:138–142.
    1. Gilliland D.G., Griffin J.D. Role of FLT3 in leukemia. Curr. Opin. Hematol. 2002;9:274–281. doi: 10.1097/00062752-200207000-00003.
    1. Ihle J.N. TheJanusprotein tyrosine kinases in hematopoietic cytokine signaling. Semin. Immonol. 1995;7:247–254. doi: 10.1006/smim.1995.0029.
    1. Harrison D.A., Binari R., Nahreini T.S., Gilman M., Perrimon N. Activation of a Drosophila Janus kinase (JAK) causes hematopoietic neoplasia and developmental defects. EMBO J. 1995;14:2857–2865. doi: 10.1002/j.1460-2075.1995.tb07285.x.
    1. Chow L.M.L., Veillette A. The Src and Csk families of tyrosine protein kinases in hemopoietic cells. Semin. Immonol. 1995;7:207–226. doi: 10.1006/smim.1995.0026.
    1. Corey S.J., Anderson S.M. Src-related protein tyrosine kinases in hematopoiesis. Blood. 1999;93:1–14.
    1. Ingley E. Src family kinases: Regulation of their activities, levels and identification of new pathways. Biochim. Biophys. Acta (BBA) Proteins Proteom. 2008;1784:56–65. doi: 10.1016/j.bbapap.2007.08.012.
    1. Klingmüller U., Wu H., Hsiao J.G., Toker A., Duckworth B.C., Cantley L.C., Lodish H.F. Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors. Proc. Natl. Acad. Sci. USA. 1997;94:3016–3021. doi: 10.1073/pnas.94.7.3016.
    1. Lannutti B.J., Shim M.-H., Blake N., Reems J.A., Drachman J.G. Identification and activation of Src family kinases in primary megakaryocytes. Exp. Hematol. 2003;31:1268–1274. doi: 10.1016/j.exphem.2003.09.009.
    1. Hibbs M.L., Tarlinton D.M., Armes J., Grail D., Hodgson G., Maglitto R., Stacker S.A., Dunn A.R. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell. 1995;83:301–311. doi: 10.1016/0092-8674(95)90171-X.
    1. Stein P.L., Vogel H., Soriano P. Combined deficiencies of Src, Fyn, and Yes tyrosine kinases in mutant mice. Genes Dev. 1994;8:1999–2007. doi: 10.1101/gad.8.17.1999.
    1. Lowell C.A., Niwa M., Soriano P., Varmus H.E. Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. Blood. 1996;87:1780–1792.
    1. Roche S., Koegl M., Barone M.V., Roussel M.F., Courtneidge S.A. DNA synthesis induced by some but not all growth factors requires Src family protein tyrosine kinases. Mol. Cell Biol. 1995;15:1102–1109. doi: 10.1128/MCB.15.2.1102.
    1. Corey S.J., Dombrosky-Ferlan P.M., Zuo S., Krohn E., Donnenberg A.D., Zorich P., Romero G., Takata M., Kurosaki T. Requirement of src kinase lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J. Biol. Chem. 1998;273:3230–3235. doi: 10.1074/jbc.273.6.3230.
    1. Linnekin D., DeBerry C.S., Mou S. Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells. J. Biol. Chem. 1997;272:27450–27455. doi: 10.1074/jbc.272.43.27450.
    1. Mano H., Ishikawa F., Nishida J., Hirai H., Takaku F. A novel protein-tyrosine kinase, tec, is preferentially expressed in liver. Oncogene. 1990;5:1781–1786.
    1. Yang W.-C., Collette Y., Nunes J.A., Olive D. Tec kinases: A family with multiple roles in immunity. Immunity. 2000;12:373–382. doi: 10.1016/S1074-7613(00)80189-2.
    1. Vihinen M., Brandau O., Brandén L.J., Kwan S.P., Lappalainen I., Lester T., Noordzij J.G., Ochs H.D., Ollila J., Pienaar S.M., et al. BTKbase, mutation database for X-linked agammaglobulinemia (XLA) Nucleic Acids Res. 1998;26:242–247. doi: 10.1093/nar/26.1.242.
    1. Van Oers N.S.C., Weiss A. The Syk/ZAP-70 protein tyrosine kinase connection to antigen receptor signalling processes. Semin. Immonol. 1995;7:227–236. doi: 10.1006/smim.1995.0027.
    1. Latour S., Chow L.M.L., Veillette A. Differential intrinsic enzymatic activity of Syk and Zap-70 protein-tyrosine kinases. J. Biol. Chem. 1996;271:22782–22790. doi: 10.1074/jbc.271.37.22782.
    1. Efremov D.G., Laurenti L. The Syk kinase as a therapeutic target in leukemia and lymphoma. Expert Opin. Invest. Drugs. 2011;20:623–636. doi: 10.1517/13543784.2011.570329.
    1. Cheng A.M., Rowley B., Pao W., Hayday A., Bolen J.B., Pawson T. Syk tyrosine kinase required for mouse viability and B-cell development. Nature. 1995;378:303–306. doi: 10.1038/378303a0.
    1. Turner M., Joseph Mee P., Costello P.S., Williams O., Price A.A., Duddy L.P., Furlong M.T., Geahlen R.L., Tybulewicz V.L.J. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature. 1995;378:298–302. doi: 10.1038/378298a0.
    1. MacDonald I., Levy J., Pawson T. Expression of the mammalian c-fes protein in hematopoietic cells and identification of a distinct fes-related protein. Mol. Cell Biol. 1985;5:2543–2551. doi: 10.1128/MCB.5.10.2543.
    1. Yates K.E., Gasson J.C. Role of c-Fes in normal and neoplastic hematopoiesis. Stem Cell J. 1996;14:117–123. doi: 10.1002/stem.140117.
    1. Craig A.W. FES/FER kinase signaling in hematopoietic cells and leukemias. Front Biosci. 2012;17:861–875. doi: 10.2741/3961.
    1. Blume-Jensen P., Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355. doi: 10.1038/35077225.
    1. Scheijen B., Griffin J.D. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21:3314–3333. doi: 10.1038/sj.onc.1205317.
    1. Ku M., Wall M., MacKinnon R.N., Walkley C.R., Purton L.E., Tam C., Izon D., Campbell L., Cheng H.-C., Nandurkar H. Src family kinases and their role in hematological malignancies. Leuk. Lymphoma. 2015;56:577–586. doi: 10.3109/10428194.2014.907897.
    1. Morris C., Kennedy M., Heisterkamp N., Columbano-Green L., Romeril K., Groffen J., Fitzgerald P. A complex chromosome rearrangement forms the BCR-ABL fusion gene in leukemic cells with a normal karyotype. Genes Chromosomes Cancer. 1991;3:263–271. doi: 10.1002/gcc.2870030405.
    1. Patel J.P., Gonen M., Figueroa M.E., Fernandez H., Sun Z., Racevskis J., Van Vlierberghe P., Dolgalev I., Thomas S., Aminova O., et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012;366:1079–1089. doi: 10.1056/NEJMoa1112304.
    1. Kaushansky K. On the molecular origins of the chronic myeloproliferative disorders: It all makes sense. Blood. 2005;105:4187–4190. doi: 10.1182/blood-2005-03-1287.
    1. James C., Ugo V., Le Couedic J.P., Staerk J., Delhommeau F., Lacout C., Garcon L., Raslova H., Berger R., Bennaceur-Griscelli A., et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–1148. doi: 10.1038/nature03546.
    1. Deschler B., Lübbert M. Acute myeloid leukemia: Epidemiology and etiology. Int. J. Am. Cancer Soc. 2006;107:2099–2107. doi: 10.1002/cncr.22233.
    1. Bullinger L., Döhner K., Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J. Clin. Oncol. 2017;35:934–946. doi: 10.1200/JCO.2016.71.2208.
    1. Hahn C.K., Berchuck J.E., Ross K.N., Kakoza R.M., Clauser K., Schinzel A.C., Ross L., Galinsky I., Davis T.N., Silver S.J., et al. Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell. 2009;16:281–294. doi: 10.1016/j.ccr.2009.08.018.
    1. Puissant A., Fenouille N., Alexe G., Pikman Y., Bassil C.F., Mehta S., Du J., Kazi J.U., Luciano F., Rönnstrand L., et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell. 2014;25:226–242. doi: 10.1016/j.ccr.2014.01.022.
    1. Farge T., Saland E., de Toni F., Aroua N., Hosseini M., Perry R., Bosc C., Sugita M., Stuani L., Fraisse M., et al. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov. 2017;7:716–735. doi: 10.1158/-16-0441.
    1. Kainz B., Heintel D., Marculescu R., Schwarzinger I., Sperr W., Le T., Weltermann A., Fonatsch C., Haas O.A., Mannhalter C., et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16) Hematol. J. 2002;3:283–289. doi: 10.1038/sj.thj.6200196.
    1. Stirewalt D.L., Radich J.P. The role of FLT3 in haematopoietic malignancies. Nat. Rev. Cancer. 2003;3:650–665. doi: 10.1038/nrc1169.
    1. Toffalini F., Demoulin J.-B. New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases. Blood. 2010;116:2429–2437. doi: 10.1182/blood-2010-04-279752.
    1. Whitman S.P., Maharry K., Radmacher M.D., Becker H., Mrozek K., Margeson D., Holland K.B., Wu Y.Z., Schwind S., Metzeler K.H., et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: A cancer and leukemia group B study. Blood. 2010;116:3622–3626. doi: 10.1182/blood-2010-05-283648.
    1. Sharma M., Ravandi F., Bayraktar U.D., Chiattone A., Bashir Q., Giralt S., Chen J., Qazilbash M., Kebriaei P., Konopleva M., et al. Treatment of FLT3-ITD-positive acute myeloid leukemia relapsing after allogeneic stem cell transplantation with Sorafenib. Biol. Blood Marrow Transplant. 2011;17:1874–1877. doi: 10.1016/j.bbmt.2011.07.011.
    1. Kindler T., Lipka D.B., Fischer T. FLT3 as a therapeutic target in AML: Still challenging after all these years. Blood. 2010;116:5089–5102. doi: 10.1182/blood-2010-04-261867.
    1. Grunwald M.R., Levis M.J. FLT3 inhibitors for acute myeloid leukemia: A review of their efficacy and mechanisms of resistance. Int. J. Hematol. 2013;97:683–694. doi: 10.1007/s12185-013-1334-8.
    1. Levis M., Allebach J., Tse K.F., Zheng R., Baldwin B.R., Smith B.D., Jones-Bolin S., Ruggeri B., Dionne C., Small D. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99:3885–3891. doi: 10.1182/blood.V99.11.3885.
    1. Levis M., Ravandi F., Wang E.S., Baer M.R., Perl A., Coutre S., Erba H., Stuart R.K., Baccarani M., Cripe L.D., et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011;117:3294–3301. doi: 10.1182/blood-2010-08-301796.
    1. Rahmani M., Davis E.M., Bauer C., Dent P., Grant S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J. Biol. Chem. 2005;280:35217–35227. doi: 10.1074/jbc.M506551200.
    1. Zhang W., Konopleva M., Ruvolo V.R., McQueen T., Evans R.L., Bornmann W.G., McCubrey J., Cortes J., Andreeff M. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia. 2008;22:808–818. doi: 10.1038/sj.leu.2405098.
    1. Burchert A., Bug G., Finke J., Stelljes M., Rollig C., Wäsch R., Bornhauser M., Berg T., Lang F., Ehninger G., et al. Sorafenib as maintenance therapy post allogeneic stem cell transplantation for FLT3-ITD positive AML: Results from the randomized, double-blind, placebo-controlled multicentre sormain trial. Blood. 2018;132:661.
    1. Mathew N.R., Baumgartner F., Braun L., O’Sullivan D., Thomas S., Waterhouse M., Muller T.A., Hanke K., Taromi S., Apostolova P., et al. Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat. Med. 2018;24:282. doi: 10.1038/nm.4484.
    1. Weisberg E., Boulton C., Kelly L.M., Manley P., Fabbro D., Meyer T., Gilliland D.G., Griffin J.D. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433–443. doi: 10.1016/S1535-6108(02)00069-7.
    1. Stone R.M., Manley P.W., Larson R.A., Capdeville R. Midostaurin: Its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018;2:444–453. doi: 10.1182/bloodadvances.2017011080.
    1. O’Farrell A.-M., Abrams T.J., Yuen H.A., Ngai T.J., Louie S.G., Yee K.W.H., Wong L.M., Hong W., Lee L.B., Town A., et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605.
    1. Fiedler W., Serve H., Dohner H., Schwittay M., Ottmann O.G., O’Farrell A.-M., Bello C.L., Allred R., Manning W.C., Cherrington J.M., et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105:986–993. doi: 10.1182/blood-2004-05-1846.
    1. Fiedler W., Kayser S., Kebenko M., Janning M., Krauter J., Schittenhelm M., Gotze K., Weber D., Gohring G., Teleanu V., et al. A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations. Br. J. Haematol. 2015;169:694–700. doi: 10.1111/bjh.13353.
    1. Zarrinkar P.P., Gunawardane R.N., Cramer M.D., Gardner M.F., Brigham D., Belli B., Karaman M.W., Pratz K.W., Pallares G., Chao Q., et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML) Blood. 2009;114:2984–2992. doi: 10.1182/blood-2009-05-222034.
    1. Levis M. Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia. Future Oncol. 2014;10:1571–1579. doi: 10.2217/fon.14.105.
    1. Altman J.K., Foran J.M., Pratz K.W., Trone D., Cortes J.E., Tallman M.S. Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am. J. Hematol. 2013;93:213–221. doi: 10.1002/ajh.24974.
    1. Hills R.K., Gammon G., Trone D., Burnett A.K. Quizartinib significantly improves overall survival in FLT3-ITD positive AML patients relapsed after stem cell transplantation or after failure of salvage chemotherapy: A comparison with historical AML database (UK NCRI data) Blood. 2015;126:2557.
    1. Cortes J., Perl A.E., Dohner H., Kantarjian H., Martinelli G., Kovacsovics T., Rousselot P., Steffen B., Dombret H., Estey E., et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: An open-label, multicentre, single-arm, phase 2 trial. Lancet. 2018;19:889–903. doi: 10.1016/S1470-2045(18)30240-7.
    1. Cortes J.E., Khaled S.K., Martinelli G., Perl A.E., Ganguly S., Russell N.H., Kramer A., Dombret H., Hogge D., Jonas B.A., et al. Efficacy and safety of single-agent Quizartinib (Q), a potent and selective FLT3 inhibitor (FLT3i), in patients (pts) with FLT3-internal tandem duplication (FLT3-ITD)-mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) enrolled in the global, phase 3, randomized controlled quantum-R trial. Blood. 2018;132:563.
    1. Zimmerman E.I., Turner D.C., Buaboonnam J., Hu S., Orwick S., Roberts M.S., Janke L.J., Ramachandran A., Stewart C.F., Inaba H., et al. Crenolanib is active against models of drug-resistant FLT3-ITD−positive acute myeloid leukemia. Blood. 2013;122:3607–3615. doi: 10.1182/blood-2013-07-513044.
    1. Galanis A., Ma H., Rajkhowa T., Ramachandran A., Small D., Cortes J., Levis M. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123:94–100. doi: 10.1182/blood-2013-10-529313.
    1. Randhawa J.K., Kantarjian H.M., Borthakur G., Thompson P.A., Konopleva M., Daver N., Pemmaraju N., Jabbour E., Kadia T.M., Estrov Z., et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations. Blood. 2014;124:389.
    1. Jorge E.C., Hagop M.K., Tapan M.K., Gautam B., Marina K., Guillermo G.-M., Naval Guastad D., Naveen P., Elias J., Zeev E., et al. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML. J. Clin. Oncol. 2016;34:7008.
    1. Zhang H., Savage S., Schultz A.R., Bottomly D., White L., Segerdell E., Wilmot B., McWeeney S.K., Eide C.A., Nechiporuk T., et al. Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat. Commun. 2019;10:244. doi: 10.1038/s41467-018-08263-x.
    1. Levis M., Alexander E.P., Jessica K.A., Jorge E.C., Ellen K.R., Richard A.L., Catherine Choy S., Eunice S.W., Stephen Anthony S., Maria R.B., et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) J. Clin. Oncol. 2015;33:7003. doi: 10.1200/jco.2015.33.15_suppl.7003.
    1. Perl A.E., Altman J.K., Cortes J., Smith C., Litzow M., Baer M.R., Claxton D., Erba H.P., Gill S., Goldberg S., et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: A multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18:1061–1075. doi: 10.1016/S1470-2045(17)30416-3.
    1. McMahon C.M., Ferng T., Canaani J., Wang E.S., Morrissette J.J.D., Eastburn D.J., Pellegrino M., Durruthy-Durruthy R., Watt C.D., Asthana S., et al. Clonal selection with Ras pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia. Cancer Discov. 2019 doi: 10.1158/-18-1453.
    1. Perl A., Martinelli G., Cortes J. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the phase III ADMIRAL trial; Proceedings of the AACR Annual Meeting; Atlanta, GA, USA. 29 March–3 April 2019.
    1. Nakatani T., Uda K., Yamaura T., Takasaki M., Akashi A., Chen F., Ishikawa Y., Hayakawa F., Hagiwara S., Kiyoi H., et al. Development of FF-10101, a novel irreversible FLT3 inhibitor, which overcomes drug resistance mutations. Blood. 2015;126:1353.
    1. Yamaura T., Nakatani T., Uda K., Ogura H., Shin W., Kurokawa N., Saito K., Fujikawa N., Date T., Takasaki M., et al. A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations. Blood. 2018;131:426–438. doi: 10.1182/blood-2017-05-786657.
    1. Ikeda H., Kanakura Y., Tamaki T., Kuriu A., Kitayama H., Ishikawa J., Kanayama Y., Yonezawa T., Tarui S., Griffin J.D. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood. 1991;78:2962–2968.
    1. Cairoli R., Beghini A., Grillo G., Nadali G., Elice F., Ripamonti C.B., Colapietro P., Nichelatti M., Pezzetti L., Lunghi M., et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: An Italian retrospective study. Blood. 2006;107:3463–3468. doi: 10.1182/blood-2005-09-3640.
    1. Malaise M., Steinbach D., Corbacioglu S. Clinical implications of c-Kit mutations in acute myelogenous leukemia. Curr. Hematol. Malig. Rep. 2009;4:77–82. doi: 10.1007/s11899-009-0011-8.
    1. Ashman L.K., Griffith R. Therapeutic targeting of c-KIT in cancer. Expert Opin. Invest. Drugs. 2013;22:103–115. doi: 10.1517/13543784.2013.740010.
    1. Lennartsson J., Jelacic T., Linnekin D., Shivakrupa R. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005;23:16–43. doi: 10.1634/stemcells.2004-0117.
    1. Chen W., Xie H., Wang H., Chen L., Sun Y., Chen Z., Li Q. Prognostic significance of KIT mutations in core-binding factor acute myeloid leukemia: A systematic review and meta-analysis. PLoS ONE. 2016;11:e0146614. doi: 10.1371/journal.pone.0146614.
    1. Ayatollahi H., Shajiei A., Sadeghian M.H., Sheikhi M., Yazdandoust E., Ghazanfarpour M., Shams S.F., Shakeri S. Prognostic importance of C-KIT mutations in core binding factor acute myeloid leukemia: A systematic review. Hematol. Oncol. Stem Cell Ther. 2017;10:1–7. doi: 10.1016/j.hemonc.2016.08.005.
    1. Dos Santos C., McDonald T., Ho Y.W., Liu H., Lin A., Forman S.J., Kuo Y.-H., Bhatia R. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents. Blood. 2013;122:1900–1913. doi: 10.1182/blood-2012-11-466425.
    1. Heo S.-K., Noh E.-K., Kim J.Y., Jeong Y.K., Jo J.-C., Choi Y., Koh S., Baek J.H., Min Y.J., Kim H. Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death. Sci. Rep. 2017;7:15278. doi: 10.1038/s41598-017-15492-5.
    1. Fiedler W., Mesters R., Tinnefeld H., Loges S., Staib P., Dührsen U., Flasshove M., Ottmann O.G., Jung W., Cavalli F., et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood. 2003;102:2763–2767. doi: 10.1182/blood-2002-10-2998.
    1. Smolich B.D., Yuen H.A., West K.A., Giles F.J., Albitar M., Cherrington J.M. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood. 2001;97:1413–1421. doi: 10.1182/blood.V97.5.1413.
    1. Linger R.M.A., Keating A.K., Earp H.S., Graham D.K. TAM receptor tyrosine kinases: Biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 2008;100:35–83.
    1. Neubauer A., O’Bryan J.P., Fiebeler A., Schmidt C., Huhn D., Liu E.T. Axl, a novel receptor tyrosine kinase isolated from chronic myelogenous leukemia. Semin. Hematol. 1993;30:34.
    1. Caberoy N.B., Zhou Y., Li W. Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. EMBO J. 2010;29:3898–3910. doi: 10.1038/emboj.2010.265.
    1. Schoumacher M., Burbridge M. Key roles of AXL and MER receptor tyrosine kinases in resistance to multiple anticancer therapies. Curr. Oncol. Rep. 2017;19:19. doi: 10.1007/s11912-017-0579-4.
    1. Graham D.K., DeRyckere D., Davies K.D., Earp H.S. The TAM family: Phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer. Nat. Rev. Cancer. 2014;14:769–785. doi: 10.1038/nrc3847.
    1. Mollard A., Warner S.L., Call L.T., Wade M.L., Bearss J.J., Verma A., Sharma S., Vankayalapati H., Bearss D.J. Design, synthesis and biological evaluation of a series of novel Axl kinase inhibitors. ACS Med. Chem. Lett. 2011;2:907–912. doi: 10.1021/ml200198x.
    1. Rochlitz C., Lohri A., Bacchi M., Schmidt M., Nagel S., Fopp M., Fey M.F., Herrmann R., Neubauer A. Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): Results from a multicenter trial of the Swiss group for clinical cancer research (SAKK) Leukemia. 1999;13:1352–1358. doi: 10.1038/sj.leu.2401484.
    1. Whitman S.P., Kohlschmidt J., Maharry K., Volinia S., Mrozek K., Nicolet D., Schwind S., Becker H., Metzeler K.H., Mendler J.H., et al. GAS6 expression identifies high-risk adult AML patients: Potential implications for therapy. Leukemia. 2014;28:1252–1258. doi: 10.1038/leu.2013.371.
    1. Dufies M., Jacquel A., Belhacene N., Robert G., Cluzeau T., Luciano F., Cassuto J.P., Raynaud S., Auberger P. Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells. Oncotarget. 2011;2:874–885. doi: 10.18632/oncotarget.360.
    1. Gioia R., Leroy C., Drullion C., Lagarde V., Etienne G., Dulucq S., Lippert E., Roche S., Mahon F.X., Pasquet J.M. Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. Blood. 2011;118:2211–2221. doi: 10.1182/blood-2010-10-313692.
    1. Gioia R., Tregoat C., Dumas P.Y., Lagarde V., Prouzet-Mauleon V., Desplat V., Sirvent A., Praloran V., Lippert E., Villacreces A., et al. CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia. J. Pathol. 2015;237:14–24. doi: 10.1002/path.4561.
    1. Hong C.C., Lay J.D., Huang J.S., Cheng A.L., Tang J.L., Lin M.T., Lai G.M., Chuang S.E. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008;268:314–324. doi: 10.1016/j.canlet.2008.04.017.
    1. Ben-Batalla I., Schultze A., Wroblewski M., Erdmann R., Heuser M., Waizenegger J.S., Riecken K., Binder M., Schewe D., Sawall S., et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine cross-talk of leukemia cells with bone marrow stroma. Blood. 2013;122:2443–2452. doi: 10.1182/blood-2013-03-491431.
    1. Park I.-K., Mishra A., Chandler J., Whitman S.P., Marcucci G., Caligiuri M.A. Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: Implications for Axl as a potential therapeutic target. Blood. 2013;121:2064–2073. doi: 10.1182/blood-2012-07-444018.
    1. Park I.K., Mundy-Bosse B., Whitman S.P., Zhang X., Warner S.L., Bearss D.J., Blum W., Marcucci G., Caligiuri M.A. Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia. Leukemia. 2015;29:2382–2389. doi: 10.1038/leu.2015.147.
    1. Dumas P.-Y., Naudin C.c., Martin-Lanner2e S.V., Izac B., Casetti L., Mansier O., Rousseau B.T., Artus A., Dufossée M.L., Giese A., et al. Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5- and hypoxia- dependent up-regulation of AXL. Haematologica. 2019;104 doi: 10.3324/haematol.2018.205385.
    1. Huey M.G., Minson K.A., Earp H.S., DeRyckere D., Graham D.K. Targeting the TAM receptors in leukemia. Cancers. 2016;8:101. doi: 10.3390/cancers8110101.
    1. Gay C.M., Balaji K., Byers L.A. Giving AXL the axe: Targeting AXL in human malignancy. Br. J. Cancer. 2017;116:415–423. doi: 10.1038/bjc.2016.428.
    1. Shen Y., Chen X., He J., Liao D., Zu X. Axl inhibitors as novel cancer therapeutic agents. Life Sci. 2018;198:99–111. doi: 10.1016/j.lfs.2018.02.033.
    1. Myers S.H., Brunton V.G., Unciti-Broceta A. AXL Inhibitors in cancer: A medicinal chemistry perspective. J. Med. Chem. 2016;59:3593–3608. doi: 10.1021/acs.jmedchem.5b01273.
    1. Holland S.J., Pan A., Franci C., Hu Y., Chang B., Li W., Duan M., Torneros A., Yu J., Heckrodt T.J., et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70:1544–1554. doi: 10.1158/0008-5472.CAN-09-2997.
    1. Ghosh A.K., Secreto C., Boysen J., Sassoon T., Shanafelt T.D., Mukhopadhyay D., Kay N.E. A novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of non-receptor kinases: Implications for therapy. Blood. 2010;117:1928–1937. doi: 10.1182/blood-2010-09-305649.
    1. Loges S., Björn Tore G., Michael H., Jörg C., Carlos Enrique V., Peter P., Ben-Batalla I., Nuray A., David M., Anthony B., et al. The immunomodulatory activity of bemcentinib (BGB324): A first-in-class selective oral AXL inhibitor in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. J. Clin. Oncol. 2018;36:70. doi: 10.1200/JCO.2018.36.5_suppl.70.
    1. Loges S., Bjorn Torre G., Michael H., Ben-Batalla I., David M., Chromik J., Maxim K., Walter M.F., Jorge E.C. A first-in-patient phase I study of BGB324, a selective Axl kinase inhibitor in patients with refractory/relapsed AML and high-risk MDS. J. Clin. Oncol. 2016;34:2561. doi: 10.1200/JCO.2016.34.15_suppl.2561.
    1. Sonja L., Gjertsen B.T., Heuser M., Chromik J., Batalla I.B., Akyüz N., Micklem D., Brown A., Lorens J., Kebenko M., et al. BGB324, an orally available selective Axl inhibitor exerts anti-leukemic activity in the first-in-patient trial BGBC003 and induces unique changes in biomarker profiles. Blood. 2016;128:592.
    1. Eryildiz F., Tyner J.W. Abstract 1265: Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia. Cancer Res. 2016;76:1265.
    1. Gilmour M., Scholtz A., Ottmann O.G., Hills R.K., Knapper S., Zabkiewicz J. Axl/Mer Inhibitor ONO-9330547 As a novel therapeutic agent in a stromal co-culture model of primary acute myeloid leukaemia (AML) Blood. 2016;128:2754.
    1. Ruvolo P., Ma H., Ruvolo V., Mu H., Schober W., Yasuhiro T., Yoshizawa T., Gallardo M., Zhang X., Khoury J.D., et al. AXL inhibitor ONO-9330547 suppresses PLK1 gene and protein expression and effectively induces growth arrest and apoptosis in FLT3 ITD acute myeloid leukemia cells. Blood. 2016;128:3939.
    1. Lee-Sherick A.B., Eisenman K.M., Sather S., McGranahan A., Armistead P.M., McGary C.S., Hunsucker S.A., Schlegel J., Martinson H., Cannon C., et al. Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia. Oncogene. 2013;32:5359. doi: 10.1038/onc.2013.40.
    1. Minson K.A., Huey M.G., Hill A.A., Perez I., Wang X., Frye S., Earp H.S., DeRyckere D., Graham D.K. Bone marrow stromal cell mediated resistance to mertk inhibition in acute leukemia. Blood. 2016;128:2819.
    1. Ruvolo P.P., Ma H., Ruvolo V.R., Zhang X., Mu H., Schober W., Hernandez I., Gallardo M., Khoury J.D., Cortes J., et al. Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms. Haematologica. 2017;102:2048–2057. doi: 10.3324/haematol.2017.168856.
    1. Tanaka K., Li C., Hirosaki T., Kato H., Ishikawa Y., Oka M., Egawa H., Kozaki R., Yoshizawa T. Abstract 1883: A novel Axl and Mertk dual inhibitor ONO-7475: A new therapeutic agent for the treatment of FLT3-ITD and -wild-type acute myeloid leukemia (AML) overexpressing. Cancer Res. 2018;78:1883.
    1. Lu J.W., Wang A.N., Liao H.A., Chen C.Y., Hou H.A., Hu C.Y., Tien H.F., Ou D.L., Lin L.I. Cabozantinib is selectively cytotoxic in acute myeloid leukemia cells with FLT3-internal tandem duplication (FLT3-ITD) Cancer Lett. 2016;376:218–225. doi: 10.1016/j.canlet.2016.04.004.
    1. Fathi A.T., Blonquist T.M., Hernandez D., Amrein P.C., Ballen K.K., McMasters M., Avigan D.E., Joyce R., Logan E.K., Hobbs G., et al. Cabozantinib is well tolerated in acute myeloid leukemia and effectively inhibits the resistance-conferring FLT3/tyrosine kinase domain/F691 mutation. Cancer. 2018;124:306–314. doi: 10.1002/cncr.31038.
    1. Jimbo T., Taira T., Komatsu T., Kumazawa K., Maeda N., Haginoya N., Suzuki T., Ota M., Totoki Y., Wada C., et al. DS-1205b, a novel, selective, small-molecule inhibitor of AXL, delays the onset of resistance and overcomes acquired resistance to EGFR-TKIs in a human EGFR-mutant NSCLC (T790M-negative) xenograft model. Ann. Oncol. 2017;28:395. doi: 10.1093/annonc/mdx367.029.
    1. Oellerich T., Oellerich M.F., Engelke M., Munch S., Mohr S., Nimz M., Hsiao H.-H., Corso J., Zhang J., Bohnenberger H., et al. b2 integrine derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis. Blood. 2013;121:3889–3899. doi: 10.1182/blood-2012-09-457887.
    1. Boros K., Puissant A., Back M., Alexe G., Bassil C.F., Sinha P., Tholouli E., Stegmaier K., Byers R.J., Rodig S.J. Increased SYK activity is associated with unfavorable outcome among patients with acute myeloid leukemia. Oncotarget. 2015;6:25575–25587. doi: 10.18632/oncotarget.4669.
    1. Bartaula-Brevik S., Lindstad Brattas M.K., Tvedt T.H.A., Reikvam H., Bruserud O. Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia. Expert Opin. Invest. Drugs. 2018;27:377–387. doi: 10.1080/13543784.2018.1459562.
    1. Richine B.M., Virts E.L., Bowling J.D., Ramdas B., Mali R., Naoye R., Liu Z., Zhang Z.Y., Boswell H.S., Kapur R., et al. Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia. Leukemia. 2016;30:2094–2097. doi: 10.1038/leu.2016.131.
    1. Walker A.R., Bhatnagar B., Marcondes A.M.Q., DiPaolo J., Vasu S., Mims A.S., Klisovic R.B., Walsh K.J., Canning R., Behbehani G.K., et al. Interim results of a phase 1b/2 study of entospletinib (GS-9973) monotherapy and in combination with chemotherapy in patients with acute myeloid leukemia. Blood. 2016;128:2831.
    1. Walker A.R., Byrd J.C., Blum W., Lin T., Crosswell H.E., Zhang D., Gao J., Rao A.V., Minden M.D., Stock W. Abstract 819: High response rates with entospletinib in patients with t(v;11q23.3)KMT2A rearranged acute myeloid leukemia and acute lymphoblastic leukemia. Cancer Res. 2018;78:819.
    1. Jie Y., Jessica H., Matthew T., Helen H., Stephen T., Mengkun Z., Karuppiah K. Anti-tumor activity of TAK-659, a dual inhibitor of SYK and FLT-3 kinases, in AML models. J. Clin. Oncol. 2016;34:e14091.
    1. Kaplan J.B., Bixby D.L., Morris J.C., Frankfurt O., Altman J., Wise-Draper T., Burke P.W., Collins S., Kannan K., Wang L., et al. A phase 1b/2 study of TAK-659, an investigational dual SYK and FLT-3 inhibitor, in patients (Pts) with relapsed or refractory acute myelogenous leukemia (R/R AML) Blood. 2016;128:2834.
    1. Ozawa Y., Williams A.H., Estes M.L., Matsushita N., Boschelli F., Jove R., List A.F. Src family kinases promote AML cell survival through activation of signal transducers and activators of transcription (STAT) Leuk. Res. 2008;32:893–903. doi: 10.1016/j.leukres.2007.11.032.
    1. Marhall A., Kazi J.U., Ronnstrand L. The Src family kinase LCK cooperates with oncogenic FLT3/ITD in cellular transformation. Sci. Rep. 2017;7:13734. doi: 10.1038/s41598-017-14033-4.
    1. Roginskaya V., Zuo S., Caudell E., Nambudiri G., Kraker A.J., Corey S.J. Therapeutic targeting of Src-kinase Lyn in myeloid leukemic cell growth. Leukemia. 1999;13:855–861. doi: 10.1038/sj.leu.2401429.
    1. Hussein K., von Neuhoff N., Büsche G., Buhr T., Kreipe H., Bock O. Opposite expression pattern of Src kinase Lyn in acute and chronic haematological malignancies. Ann. Hematol. 2009;88:1059–1067. doi: 10.1007/s00277-009-0727-5.
    1. Robinson L.J., Xue J., Corey S.J. Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations. Exp. Hematol. 2005;33:469–479. doi: 10.1016/j.exphem.2005.01.004.
    1. Dos Santos C., Demur C., Bardet V., Prade-Houdellier N., Payrastre B., Recher C. A critical role for Lyn in acute myeloid leukemia. Blood. 2008;111:2269–2279. doi: 10.1182/blood-2007-04-082099.
    1. Okamoto M., Hayakawa F., Miyata Y., Watamoto K., Emi N., Abe A., Kiyoi H., Towatari M., Naoe T. Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD. Leukemia. 2007;21:403–410. doi: 10.1038/sj.leu.2404547.
    1. Leischner H., Albers C., Grundler R., Razumovskaya E., Spiekermann K., Bohlander S., Ronnstrand L., Gotze K., Peschel C., Duyster J. SRC is a signaling mediator in FLT3-ITD- but not in FLT3-TKD-positive AML. Blood. 2012;119:4026–4033. doi: 10.1182/blood-2011-07-365726.
    1. Ingley E. Functions of the Lyn tyrosine kinase in health and disease. Cell Commun. Sign. CCS. 2012;10:21. doi: 10.1186/1478-811X-10-21.
    1. Leischner H., Grundler R., Albers C., Illert A.L., Gotze K., Peschel C., Duyster J. Combination of c-SRC and FLT3 inhibitors has an additive inhibitory effect on FLT3 ITD but not on FLT3 TKD positive cells. Blood. 2010;116:2892.
    1. Gozgit J.M., Wong M.J., Wardwell S., Tyner J.W., Loriaux M.M., Mohemmad Q.K., Narasimhan N.I., Shakespeare W.C., Wang F., Druker B.J., et al. Potent activity of Ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol. Cancer Ther. 2011;10:1028–1035. doi: 10.1158/1535-7163.MCT-10-1044.
    1. Bourrié B., Brassard D.L., Cosnier-Pucheu S., Zilberstein A., Yu K., Levit M., Morrison J.G., Perreaut P., Jegham S., Hilairet S., et al. SAR103168: A tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias. Leuk. Lymphoma. 2013;54:1488–1499. doi: 10.3109/10428194.2012.745071.
    1. Weir M.C., Hellwig S., Tan L., Liu Y., Gray N.S., Smithgall T.E. Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth. PLoS ONE. 2017;12:e0181178. doi: 10.1371/journal.pone.0181178.
    1. Weir M.C., Shu S.T., Patel R.K., Hellwig S., Chen L., Tan L., Gray N.S., Smithgall T.E. Selective inhibition of the myeloid Src-family kinase Fgr potently suppresses AML cell growth in vitro and in vivo. ACS Chem. Biol. 2018;13:1551–1559. doi: 10.1021/acschembio.8b00154.
    1. Kentsis A., Reed C., Rice K.L., Sanda T., Rodig S.J., Tholouli E., Christie A., Valk P.J.M., Delwel R., Ngo V., et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat. Med. 2012;18:1118–1122. doi: 10.1038/nm.2819.
    1. Fialin C., Larrue C., Vergez F., Sarry J.E., Bertoli S., Mansat-De Mas V., Demur C., Delabesse E., Payrastre B., Manenti S., et al. The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors. Leukemia. 2013;27:325–335. doi: 10.1038/leu.2012.240.
    1. McGee S.F., Kornblau S.M., Qiu Y., Look A.T., Zhang N., Yoo S.Y., Coombes K.R., Kentsis A. Biological properties of ligand-dependent activation of the MET receptor kinase in acute myeloid leukemia. Leukemia. 2015;29:1218. doi: 10.1038/leu.2014.348.
    1. Mulgrew N.M., Kettyle L.M.J., Ramsey J.M., Cull S., Smyth L.J., Mervyn D.M., Bijl J.J., Thompson A. c-Met inhibition in a HOXA9/Meis1 model of CN-AML. Dev. Dyn. 2014;243:172–181. doi: 10.1002/dvdy.24070.
    1. Smith C.I.E., Islam T.C., Mattsson P.T., Mohamed A.J., Nore B.F., Vihinen M. The Tec family of cytoplasmic tyrosine kinases: Mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. Bioessays. 2001;23:436–446. doi: 10.1002/bies.1062.
    1. Tang B., Mano H., Yi T., Ihle J.N. Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding. Mol. Cell. Biol. 1994;14:8432–8437. doi: 10.1128/MCB.14.12.8432.
    1. Van Dijk T.B., van den Akker E., Parren-van Amelsvoort M., Mano H., Löwenberg B., von Lindern M. Stem cell factor induces phosphatidylinositol 3-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells. Blood. 2000;96:3406–3413.
    1. Rushworth S.A., Pillinger G., Abdul-Aziz A., Piddock R., Shafat M.S., Murray M.Y., Zaitseva L., Lawes M.J., MacEwan D.J., Bowles K.M. Activity of Bruton’s tyrosine-kinase inhibitor ibrutinib in patients with CD117-positive acute myeloid leukaemia: A mechanistic study using patient-derived blast cells. Lancet Haematol. 2015;2:e204–e211. doi: 10.1016/S2352-3026(15)00046-0.
    1. Pillinger G., Abdul-Aziz A., Zaitseva L., Lawes M., MacEwan D.J., Bowles K.M., Rushworth S.A. Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia. Sci. Rep. 2015;5:12949. doi: 10.1038/srep12949.
    1. Zaitseva L., Murray M.Y., Shafat M.S., Lawes M.J., MacEwan D.J., Bowles K.M., Rushworth S.A. Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget. 2014;5:9930–9938. doi: 10.18632/oncotarget.2479.
    1. Rushworth S.A., Murray M.Y., Zaitseva L., Bowles K.M., MacEwan D.J. Identification of Bruton’s tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood. 2014;123:1229–1238. doi: 10.1182/blood-2013-06-511154.
    1. Wu H., Hu C., Wang A., Weisberg E.L., Wang W., Chen C., Zhao Z., Yu K., Liu J., Wu J., et al. Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML. Leukemia. 2016;30:754–757. doi: 10.1038/leu.2015.175.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever