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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2020

Open Access 01-12-2020 | Acute Myeloid Leukemia | Review

Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia

Authors: Melat T. Gebru, Hong-Gang Wang

Published in: Journal of Hematology & Oncology | Issue 1/2020

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Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.
Literature
1.
Longo DL, Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52. CrossRef
2.
3.
4.
Licht JD, Sternberg DW. The molecular pathology of acute myeloid leukemia. Hematol Am Soc Hematol Educ Program. 2005;2005:137–42. CrossRef
5.
Steffen B, Müller-Tidow C, Schwäble J, Berdel WE, Serve H. The molecular pathogenesis of acute myeloid leukemia. Crit Rev Oncol Hematol. 2005;56:195–221. PubMedCrossRef
6.
7.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. PubMedPubMedCentralCrossRef
8.
Di Nardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology. 2016;2016:348–55. CrossRef
9.
10.
Kiyoi H, Kawashima N, Ishikawa Y. FLT3 mutations in acute myeloid leukemia: therapeutic paradigm beyond inhibitor development. Cancer Sci. 2020;111:312–22. PubMedCrossRef
11.
12.
Takahashi S. Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. J Hematol Oncol. 2011;4:13. PubMedPubMedCentralCrossRef
13.
Grafone T, Palmisano M, Nicci C, Storti S. An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev. 2012;6:e8. PubMedPubMedCentralCrossRef
14.
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 Cell. 2004;13:169–78. PubMedCrossRef
15.
Agnès F, Shamoon B, Dina C, Rosnet O, Birnbaum D, Galibert F. Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III. Gene. 1994;145:283–8. PubMedCrossRef
16.
Gotze KS, Ramirez M, Tabor K, Small D, Matthews W, Civin CI. Flt3high and Flt3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct. Blood. 1998;91:1947–58. PubMedCrossRef
17.
Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–65. PubMedCrossRef
18.
19.
Wodnar-Filipowicz A. Flt3 ligand: role in control of hematopoietic and immune functions of the bone marrow. News Physiol Sci. 2003;18:247–51. PubMed
20.
Lisovsky M, Braun SE, Ge Y, Takahira H, Lu L, Savchenko VG, et al. Flt3-ligand production by human bone marrow stromal cells. Leukemia. 1996;10:1012–8. PubMed
21.
Bruserud Ø, Hovland R, Wergeland L, Huang TS, Gjertsen BT. Flt3-mediated signaling in human acute myelogenous leukemia (AML) blasts: a functional characterization of the effects of Flt3-ligand in AML cell populations with and without genetic Flt3 abnormalities. Haematologica. 2003;88:416–28. PubMed
22.
Zhang S, Mantel C, Broxmeyer HE. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J Leukoc Biol. 1999;65:372–80. PubMedCrossRef
23.
Takahashi S. Inhibition of the MEK/MAPK signal transduction pathway strongly impairs the growth of Flt3-ITD cells. Am J Hematol. 2006;81:154–5. PubMedCrossRef
24.
Scholl C, Gilliland DG, Fröhling S. Deregulation of signaling pathways in acute myeloid leukemia. Semin Oncol. 2008;35:336–45. PubMedCrossRef
25.
Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell. 2012;22:668–82. PubMedPubMedCentralCrossRef
26.
Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwäble J, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65:9643–50. PubMedCrossRef
27.
Sargin B, Choudhary C, Crosetto N, Schmidt MHH, Grundler R, Rensinghoff M, et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood. 2007;110:1004–12. PubMedCrossRef
28.
29.
Peschel I, Podmirseg SR, Taschler M, Duyster J, Götze KS, Sill H, et al. FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia. Haematologica. 2017;102:1378–89. PubMedPubMedCentralCrossRef
30.
31.
Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–8. PubMed
32.
Lagunas-Rangel FA, Chávez-Valencia V. FLT3–ITD and its current role in acute myeloid leukaemia. Med Oncol. 2017;34:114. PubMedCrossRef
33.
Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333–7. PubMedCrossRef
34.
35.
Choudhary C, Brandts C, Schwable J, Tickenbrock L, Sargin B, Ueker A, et al. Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood. 2007;110:370–4. PubMedCrossRef
36.
Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006;108:1339–45. PubMedPubMedCentralCrossRef
37.
Takahashi S. Mutations of FLT3 receptor affect its surface glycosylation, intracellular localization, and downstream signaling. Leuk Res Rep. 2019;13:100187. PubMedPubMedCentral
38.
Schmidt-Arras D, Bohmer SA, Koch S, Müller JP, Blei L, Cornils H, et al. Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality. Blood. 2009;113:3568–76. PubMedCrossRef
39.
40.
Natarajan K, Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR. Pim-1 kinase phosphorylates and stabilizes 130 kDa FLT3 and promotes aberrant STAT5 signaling in acute myeloid leukemia with FLT3 internal tandem duplication. PLoS ONE. 2013;8:e74653. PubMedPubMedCentralCrossRef
41.
Sallmyr A, Fan J, Datta K, Kim KT, Grosu D, Shapiro P, et al. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML. Blood. 2008;111:3173–82. PubMedCrossRef
42.
Chen W, Jones D, Jeffrey Medeiros L, Luthra R, Lin P. Acute myeloid leukaemia with FLT3 gene mutations of both internal tandem duplication and point mutation type. Br J Haematol. 2005;130:726–8. PubMedCrossRef
43.
Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. 2007;110:1262–70. PubMedCrossRef
44.
Sakaguchi M, Yamaguchi H, Kuboyama M, Najima Y, Usuki K, Ueki T, et al. Significance of FLT3-tyrosine kinase domain mutation as a prognostic factor for acute myeloid leukemia. Int J Hematol. 2019;110:566–74. PubMedCrossRef
45.
Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters an analysis of 3082 patients. Blood. 2008;111:2527–37. PubMedCrossRef
46.
47.
Leick MB, Levis MJ. The future of targeting FLT3 activation in AML. Curr Hematol Maligancy Rep. 2017;12:153–67. CrossRef
48.
Smith CC, Lin K, Stecula A, Sali A, Shah NP. FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia. 2015;29:2390–2. PubMedPubMedCentralCrossRef
49.
Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018;2:444–53. PubMedPubMedCentralCrossRef
50.
51.
Caravatti G, Meyer T, Fredenhagen A, Trinks U, Mett H, Fabbro D. Inhibitory activity and selectivity of staurosporine derivatives towards protein kinase C. Bioorganic Med Chem Lett. 1994;4:399–404. CrossRef
52.
Gallogly MM, Lazarus HM, Cooper BW. Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Ther Adv Hematol. 2017;8:245–61. PubMedPubMedCentralCrossRef
53.
Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433–43. PubMedCrossRef
54.
Fischer T, Stone RM, DeAngelo DJ, Galinsky I, Estey E, Lanza C, et al. 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. 2010;28:4339–45. PubMedPubMedCentralCrossRef
55.
Propper DJ, McDonald AC, Man A, Thavasu P, Balkwill F, Braybrooke JP, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19:1485–92. PubMedCrossRef
56.
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 Mutation. N Engl J Med. 2017;377:454–64. PubMedPubMedCentralCrossRef
57.
58.
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, 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;18:1061–75. PubMedPubMedCentralCrossRef
59.
Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728–40. PubMedCrossRef
60.
61.
Breitenbuecher F, Markova B, Kasper S, Carius B, Stauder T, Böhmer FD, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009;113:4063–73. PubMedCrossRef
62.
Stölzel F, Steudel C, Oelschlägel U, Mohr B, Koch S, Ehninger G, et al. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol. 2010;89:653–62. PubMedCrossRef
63.
Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH, 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. 2006;107:293–300. PubMedCrossRef
64.
Man CH, Fung TK, Ho C, Han HHC, Chow HCH, Ma ACH, et al. Sorafenib treatment of FLT3-ITD + acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012;119:5133–43. PubMedCrossRef
65.
Alvarado Y, Kantarjian HM, Luthra R, Ravandi F, Borthakur G, Garcia-Manero G, et al. Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. Cancer. 2014;120:2142–9. PubMedCrossRef
66.
Green AS, Maciel TT, Hospital MA, Yin C, Mazed F, Townsend EC, et al. Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia. Sci Adv. 2015;1(8):e1500221. PubMedPubMedCentralCrossRef
67.
Yang X, Sexauer A, Levis M. Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase. Br J Haematol. 2014;164:61–72. PubMedCrossRef
68.
Fiedler W, Kayser S, Kebenko M, Janning M, Krauter J, Schittenhelm M, 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. PubMedCrossRef
69.
Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, et al. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013;121:3165–71. PubMedPubMedCentralCrossRef
70.
Smith CC, Wang Q, Chin C-S, Salerno S, Damon LE, Levis MJ, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485:260–3. PubMedPubMedCentralCrossRef
71.
McMahon CM, Canaani J, Rea B, Sargent RL, Morrissette JJD, Lieberman DB, et al. Mechanisms of acquired resistance to gilteritinib therapy in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood. 2017;130(Suppl 1):295.
72.
Zhang H, Savage S, Schultz AR, Bottomly D, White L, Segerdell E, et al. Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat Commun. 2019;10:244. PubMedPubMedCentralCrossRef
73.
Smith CC, Zhang C, Lin KC, Lasater EA, Zhang Y, Massi E, et al. Characterizing and overriding the structural mechanism of the quizartinib-resistant FLT3 “gatekeeper” F691L uutation with PLX3397. Cancer Discov. 2015;5:668–79. PubMedPubMedCentralCrossRef
74.
Moors I, Vandepoele K, Philippé J, Deeren D, Selleslag D, Breems D, et al. Clinical implications of measurable residual disease in AML: review of current evidence. Crit Rev Oncol Hematol. 2019;133:142–8. PubMedCrossRef
75.
76.
Intlekofer AM, Shih AH, Wang B, Nazir A, Rustenburg AS, Albanese SK, et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature. 2018;559:125–9. PubMedPubMedCentralCrossRef
77.
Ossenkoppele G, Schuurhuis GJ. MRD in AML: does it already guide therapy decision-making? Hematol Am Soc Hematol Educ Program. 2016;2016:356–65. CrossRef
78.
Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422–33. PubMedCrossRef
79.
Mori M, Kaneko N, Ueno Y, Yamada M, Tanaka R, Saito R, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Investig New Drugs. 2017;35:556–65. CrossRef
80.
Piloto O, Wright M, Brown P, Kim K-T, Levis M, Small D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood. 2007;109:1643–52. PubMedPubMedCentralCrossRef
81.
Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN, 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. 2002;100:2387–92. PubMedCrossRef
82.
83.
84.
Traer E, Martinez J, Javidi-Sharifi N, Agarwal A, Dunlap J, English I, et al. FGF2 from marrow microenvironment promotes resistance to FLT3 inhibitors in acute myeloid leukemia. Cancer Res. 2016;76:6471–82. PubMedPubMedCentralCrossRef
85.
Sung PJ, Sugita M, Koblish H, Perl AE, Carroll M. Hematopoietic cytokines mediate resistance to targeted therapy in FLT3-ITD acute myeloid leukemia. Blood Adv. 2019;3:1061–72. PubMedPubMedCentralCrossRef
86.
Chang YT, Hernandez D, Alonso S, Gao M, Su M, Ghiaur G, et al. Role of CYP3A4 in bone marrow microenvironment–mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors. Blood Adv. 2019;3:908–16. PubMedPubMedCentralCrossRef
87.
Sexauer A, Perl A, Yang X, Borowitz M, Gocke C, Rajkhowa T, et al. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITDAML. Blood. 2012;120:4205–14. PubMedPubMedCentralCrossRef
88.
McMahon CM, Canaani J, Rea B, Sargent RL, Qualtieri JN, Watt CD, et al. Gilteritinib induces differentiation in relapsed and refractory FLT3-mutated acute myeloid leukemia. Blood Adv. 2019;3:1581–5. PubMedPubMedCentralCrossRef
89.
Shaffer BC, Gillet JP, Patel C, Baer MR, Bates SE, Gottesman MM. Drug resistance: still a daunting challenge to the successful treatment of AML. Drug Resist Updates. 2012;15:62–9. CrossRef
90.
Hunter HM, Pallis M, Seedhouse CH, Grundy M, Gray C, Russell NH. 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. 2004;127:26–33. PubMedCrossRef
91.
92.
Hata AN, Niederst MJ, Archibald HL, Gomez-Caraballo M, Siddiqui FM, Mulvey HE, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22:262–9. PubMedPubMedCentralCrossRef
93.
Baker SD, Zimmerman EI, Wang Y-D, Orwick S, Zatechka DS, Buaboonnam J, et al. Emergence of polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Clin Cancer Res. 2013;19:5758–68. PubMedCrossRef
94.
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10. PubMedPubMedCentralCrossRef
95.
Krönke J, Bullinger L, Teleanu V, Tschürtz F, Gaidzik VI, Kühn MWM, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122:100–8. PubMedCrossRef
96.
Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature. 2015;520:368–72. PubMedPubMedCentralCrossRef
97.
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80. PubMedPubMedCentralCrossRef
98.
Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50. PubMedPubMedCentralCrossRef
99.
Sahu N, Stephan J-P, Cruz DD, Merchant M, Haley B, Bourgon R, et al. Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs. Nat Commun. 2016;7:12351. PubMedPubMedCentralCrossRef
100.
Ramirez M, Rajaram S, Steininger RJ, Osipchuk D, Roth MA, Morinishi LS, et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat Commun. 2016;19(7):10690. CrossRef
101.
Gebru MT, Atkinson JM, Young M, Zhang L, Tang Z, Liu Z, et al. Glucocorticoids enhance the anti-leukemic activity of FLT3 inhibitors in FLT3 mutant acute myeloid leukemia. Blood. 2020;136:1067–79. PubMedCrossRefPubMedCentral
102.
Shlush LI, Mitchell A, Heisler L, Abelson S, Ng SWK, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104–8. CrossRefPubMed
103.
104.
Vallette FM, Olivier C, Lézot F, Oliver L, Cochonneau D, Lalier L, et al. Dormant, quiescent, tolerant and persister cells: four synonyms for the same target in cancer. Biochem Pharmacol. 2019;162:169–76. PubMedCrossRef
105.
Zeijlemaker W, Grob T, Meijer R, Hanekamp D, Kelder A, Carbaat-Ham JC, et al. CD34+CD38− leukemic stem cell frequency to predict outcome in acute myeloid leukemia. Leukemia. 2019;33:1102–12. PubMedCrossRef
106.
De Angelis ML, Francescangeli F, La Torre F, Zeuner A. Stem cell plasticity and dormancy in the development of cancer therapy resistance. Front Oncol. 2019;9:626. PubMedPubMedCentralCrossRef
107.
Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA. 2011;108:7950–5. PubMedCrossRefPubMedCentral
108.
Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146:633–44. CrossRefPubMed
109.
Melgar K, Walker MM, Jones LQM, Bolanos LC, Hueneman K, Wunderlich M, et al. Overcoming adaptive therapy resistance in AML by targeting immune response pathways. Sci Transl Med. 2019;11:508. CrossRef
110.
Gurule NJ, Heasley LE. Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses. Cancer Drug Resist. 2018;1:118. PubMedPubMedCentral
111.
Mascia F, Mariani V, Girolomoni G, Pastore S. Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol. 2003;163:303–12. PubMedPubMedCentralCrossRef
112.
Mascia F, Lam G, Keith C, Garber C, Steinberg SM, Kohn E, et al. Genetic ablation of epidermal EGFR reveals the dynamic origin of adverse effects of anti-EGFR therapy. Sci Transl Med. 2013;5:199. CrossRef
113.
Song C, Piva M, Sun L, Hong A, Moriceau G, Kong X, et al. Recurrent tumor cell–intrinsic and –extrinsic alterations during mapki-induced melanoma regression and early adaptation. Cancer Discov. 2017;7:1248–65. PubMedPubMedCentralCrossRef
114.
Shen H, Kreisel D, Goldstein DR. Processes of sterile inflammation. J Immunol. 2013;191:2857–63. PubMedCrossRef
115.
Martin M, Rehani K, Jope RS, Michalek SM. Toll-like receptor—mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol. 2005;6:777–84. PubMedPubMedCentralCrossRef
116.
Zhang J, Li L, Friedman AD, Small D, Paz-Priel I. Canonical NF-κB signalling is a potential target in FLT3/ITD AML. Blood. 2012;120:2447–2447. CrossRef
Metadata
Title
Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia
Authors
Melat T. Gebru
Hong-Gang Wang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-020-00992-1

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