High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells.
Animals
Apoptosis
/ drug effects
Cell Line, Tumor
Cyclin-Dependent Kinase 4
/ antagonists & inhibitors
Cyclin-Dependent Kinase 6
/ antagonists & inhibitors
Humans
Leukemia, Myeloid, Acute
/ drug therapy
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Proteomics
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
AML
FLT3-CDK4/6 kinase
Proteomic profiling
Journal
Annals of hematology
ISSN: 1432-0584
Titre abrégé: Ann Hematol
Pays: Germany
ID NLM: 9107334
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
received:
09
02
2021
accepted:
08
03
2021
pubmed:
1
4
2021
medline:
27
5
2021
entrez:
31
3
2021
Statut:
ppublish
Résumé
FLT3 mutations, which are found in a third of patients with acute myeloid leukemia (AML), are associated with poor prognosis. Responses to currently available FLT3 inhibitors in AML patients are typically transient and followed by disease recurrence. Thus, FLT3 inhibitors with new inhibitory mechanisms are needed to improve therapeutic outcomes. AMG925 is a novel, potent, small-molecule dual inhibitor of FLT3 and CDK4/6. In this study. we determined the antileukemic effects and mechanisms of action of AMG925 in AML cell lines and primary samples, in particular AML stem/progenitor cells. AMG925 inhibited cell growth and promoted apoptosis in AML cells with or without FLT3 mutations. Reverse-phase protein array profiling confirmed its on-target effects on FLT3-CDK4/6-regulated pathways and identified unrevealed signaling network alterations in AML blasts and stem/progenitor cells in response to AMG925. Mass cytometry identified pathways that may confer resistance to AMG925 in phenotypically defined AML stem/progenitor cells and demonstrated that combined blockade of FLT3-CDK4/6 and AKT/mTOR signaling facilitated stem cell death. Our findings provide a rationale for the mechanism-based inhibition of FLT3-CDK4/6 and for combinatorial approaches to improve the efficacy of FLT3 inhibition in both FLT3 wild-type and FLT3-mutated AML.
Identifiants
pubmed: 33787984
doi: 10.1007/s00277-021-04493-0
pii: 10.1007/s00277-021-04493-0
doi:
Substances chimiques
Protein Kinase Inhibitors
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1485-1496Subventions
Organisme : NCI NIH HHS
ID : P50 CA100632
Pays : United States
Organisme : NCI NIH HHS
ID : CA155056-04
Pays : United States
Organisme : Leukemia and Lymphoma Society
ID : 6427-13
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100632
Pays : United States
Organisme : NCI NIH HHS
ID : CA155056-04
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Références
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O’Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ (2016) Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209–2221
pubmed: 4979995
pmcid: 4979995
Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D (1991) Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6(9):1641–1650
pubmed: 1656368
Rosnet O, Birnbaum D (1993) Hematopoietic receptors of class III receptor-type tyrosine kinases. Crit Rev Oncog 4(6):595–613
pubmed: 7506935
Shurin MR, Esche C, Lotze MT (1998) FLT3: receptor and ligand. Biology and potential clinical application. Cytokine Growth Factor Rev 9(1):37–48
pubmed: 9720755
Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T, Sonoda Y, Abe T, Kahsima K, Matsuo Y, Naoe T (1997) Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 11(10):1605–1609
pubmed: 9324277
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (2001) Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97(8):2434–2439
pubmed: 11290608
Fenski R, Flesch K, Serve S, Mizuki M, Oelmann E, Kratz-Albers K, Kienast J, Leo R, Schwartz S, Berdel WE, Serve H (2000) Constitutive activation of FLT3 in acute myeloid leukaemia and its consequences for growth of 32D cells. Br J Haematol 108(2):322–330
pubmed: 10691863
Tse KF, Mukherjee G, Small D (2000) Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia 14(10):1766–1776
pubmed: 11021752
Daver N, Schlenk RF, Russell NH, Levis MJ (2019) Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 33(2):299–312
pubmed: 30651634
pmcid: 6365380
Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M (2010) FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 115(7):1425–1432
pubmed: 20007803
pmcid: 2826764
Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, Zarrinkar PP, Schadt EE, Kasarskis A, Kuriyan J, Shah NP (2012) Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485(7397):260–263
pubmed: 22504184
pmcid: 3390926
Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O’Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150(2):264–278
pubmed: 3407563
pmcid: 3407563
Li Z, Wang X, Eksterowicz J, Gribble MW Jr, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC (2014) Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3. J Med Chem 57(8):3430–3449
pubmed: 24641103
Keegan K, Li C, Li Z, Ma J, Ragains M, Coberly S, Hollenback D, Eksterowicz J, Liang L, Weidner M, Huard J, Wang X, Alba G, Orf J, Lo MC, Zhao S, Ngo R, Chen A, Liu L, Carlson T, Quéva C, McGee LR, Medina J, Kamb A, Wickramasinghe D, Dai K (2014) Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia. Mol Cancer Ther 13(4):880–889
pubmed: 24526162
Tibes R, Qiu YH, Lu Y, Hennessy B, Andreeff M, Mills GB, Kornblau SM (2006) Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells. Mol Cancer Ther 5(10):2512–2521
pubmed: 17041095
Bendall SC, Simonds EF, Qiu P, Amir EAD, Krutzik PO, Finck R, Bruggner RV, Melamed R, Trejo A, Ornatsky OI, Balderas RS, Plevritis SK, Sachs K, Pe'er D, Tanner SD, Nolan GP (2011) Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332(6030):687–696
pubmed: 21551058
pmcid: 3273988
Kojima K, Konopleva M, McQueen T, O'Brien S, Plunkett W, Andreeff M (2006) Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood 108(3):993–1000
pubmed: 16543464
pmcid: 1895860
Zeng Z, Samudio IJ, Zhang W, Estrov Z, Pelicano H, Harris D, Frolova O, Hail N Jr, Chen W, Kornblau SM, Huang P, Lu Y, Mills GB, Andreeff M, Konopleva M (2006) Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res 66(7):3737–3746
pubmed: 16585200
Kornblau SM, Tibes R, Qiu YH, Chen W, Kantarjian HM, Andreeff M, Coombes KR, Mills GB (2009) Functional proteomic profiling of AML predicts response and survival. Blood 113(1):154–164
pubmed: 18840713
pmcid: 2951831
Hu J, He X, Baggerly KA, Coombes KR, Hennessy BTJ, Mills GB (2007) Non-parametric quantification of protein lysate arrays. Bioinformatics 23(15):1986–1994
pubmed: 17599930
Neeley ES, Baggerly KA, Kornblau SM (2012) Surface adjustment of reverse phase protein arrays using positive control spots. Cancer Informat 11:77–86
Han L, Qiu P, Zeng Z, Jorgensen JL, Mak DH, Burks JK, Schober W, McQueen TJ, Cortes J, Tanner SD, Roboz GJ, Kantarjian HM, Kornblau SM, Guzman ML, Andreeff M, Konopleva M (2015) Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells. Cytometry A 87(4):346–356
pubmed: 25598437
pmcid: 4388314
Zeng Z, Konopleva M, Andreeff M (2017) Single-cell mass cytometry of acute myeloid leukemia and leukemia stem/progenitor cells. Methods Mol Biol 1633:75–86
pubmed: 28735481
Finck R et al (2013) Normalization of mass cytometry data with bead standards. Cytometry A 83(5):483–494
pubmed: 23512433
pmcid: 3688049
Chen H, Lau MC, Wong MT, Newell EW, Poidinger M, Chen J (2016) Cytofkit: A bioconductor package for an integrated mass cytometry data analysis pipeline. PLoS Comput Biol 12(9):e1005112
pubmed: 27662185
pmcid: 5035035
Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737
pubmed: 9212098
Lankat-Buttgereit B, Goke R (2009) The tumour suppressor Pdcd4: recent advances in the elucidation of function and regulation. Biol Cell 101(6):309–317
pubmed: 19356152
Concannon CG, Gorman AM, Samali A (2003) On the role of Hsp27 in regulating apoptosis. Apoptosis 8(1):61–70
pubmed: 12510153
Pollyea DA, Gutman JA, Gore L, Smith CA, Jordan CT (2014) Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials. Haematologica 99(8):1277–1284
pubmed: 25082785
pmcid: 4116825
Blank U, Karlsson S (2011) The role of Smad signaling in hematopoiesis and translational hematology. Leukemia 25(9):1379–1388
pubmed: 21566654
Kentsis A, Reed C, Rice KL, Sanda T, Rodig SJ, Tholouli E, Christie A, Valk PJM, Delwel R, Ngo V, Kutok JL, Dahlberg SE, Moreau LA, Byers RJ, Christensen JG, Woude GV, Licht JD, Kung AL, Staudt LM, Look AT (2012) Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat Med 18(7):1118–1122
pubmed: 22683780
pmcid: 3438345
Luo JM, Yoshida H, Komura S, Ohishi N, Pan L, Shigeno K, Hanamura I, Miura K, Iida S, Ueda R, Naoe T, Akao Y, Ohno R, Ohnishi K (2003) Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia 17(1):1–8
pubmed: 12529653
Zeng Z, Wang RY, Qiu YH, Mak DH, Coombes K, Yoo SY, Zhang Q, Jessen K, Liu Y, Rommel C, Fruman DA, Kantarjian HM, Kornblau SM, Andreeff M, Konopleva M (2016) MLN0128, a novel mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML and AML stem/ progenitor cells. Oncotarget 7(34):55083–55097
pubmed: 27391151
pmcid: 5342403
Tsapogas P et al (2017) Int J Mol Sci 18(6)
Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y, Miyawaki S, Kuriyama K, Shimazaki C, Akiyama H, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Ueda R, Ohno R, Emi N, Naoe T (2004) Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 103(5):1901–1908
pubmed: 14604973
Grunwald MR, Levis MJ (2013) FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance. Int J Hematol 97(6):683–694
pubmed: 23613268
Culter G, Fridman JS (2016) A machine-learning analysis suggests that FLX925, a FLT3/CDK4/6 kinase inhibitor, is potent against FLT3-wild type tumors via its CDK4/6 activity. Blood 128(22):3520
Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98(6):1752–1759
Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH, Brandts C, Serve H, Roesel J, Giles F, Feldman E, Ehninger G, Schiller GJ, Nimer S, Stone RM, Wang Y, Kindler T, Cohen PS, Huber C, Fischer T (2006) Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 107(1):293–300
pubmed: 16150941
Kindler T et al (2005) Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML). Blood 105(1):335–340
pubmed: 15345593
Koga F, Xu W, Karpova TS, McNally JG, Baron R, Neckers L (2006) Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation. Proc Natl Acad Sci U S A 103(30):11318–11322
pubmed: 16844778
pmcid: 1544084
Yang L et al (2013) Hsp27: a novel therapeutic target for pediatric M4/M5 acute myeloid leukemia. Oncol Rep 29(4):1459–1466
pubmed: 23404246
Wu S, Akhtari M, Alachkar H (2018) Characterization of mutations in the mitochondrial encoded electron transport chain complexes in acute myeloid leukemia. Sci Rep 8(1):13301
pubmed: 30185817
pmcid: 6125587
Magliulo D, Bernardi R, Messina S (2018) Lysine-specific demethylase 1A as a Promising target in acute myeloid leukemia. Front Oncol 8:255
pubmed: 30073149
pmcid: 6060236
Zhang W, Gao C, Konopleva M, Chen Y, Jacamo RO, Borthakur G, Cortes JE, Ravandi F, Ramachandran A, Andreeff M (2014) Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies. Clin Cancer Res 20(9):2363–2374
pubmed: 24619500
pmcid: 4073635
Zhang W, Ruvolo VR, Gao C, Zhou L, Bornmann W, Tsao T, Schober WD, Smith P, Guichard S, Konopleva M, Andreeff M (2014) Evaluation of apoptosis induction by concomitant inhibition of MEK, mTOR, and Bcl-2 in human acute myelogenous leukemia cells. Mol Cancer Ther 13(7):1848–1859
pubmed: 24739393
pmcid: 4090272
Machado-Neto JA et al (2018) Insulin substrate receptor (IRS) proteins in normal and malignant hematopoiesis. Clinics (Sao Paulo) 73(suppl 1):e566s
Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, Park S, Green AS, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, Bouscary D (2010) Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica 95(3):415–423
pubmed: 20007139