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Expression of myeloid Src-family kinases is associated with poor prognosis in AML and influences Flt3-ITD kinase inhibitor acquired resistance


Autoři: Ravi K. Patel aff001;  Mark C. Weir aff001;  Kexin Shen aff001;  Daniel Snyder aff001;  Vaughn S. Cooper aff001;  Thomas E. Smithgall aff001
Působiště autorů: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America aff001
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225887

Souhrn

Unregulated protein-tyrosine kinase signaling is a common feature of AML, often involving mutations in Flt3 and overexpression of myeloid Src-family kinases (Hck, Fgr, Lyn). Here we show that high-level expression of these Src kinases predicts poor survival in a large cohort of AML patients. To test the therapeutic benefit of Flt3 and Src-family kinase inhibition, we used the pyrrolopyrimidine kinase inhibitor A-419259. This compound potently inhibits Hck, Fgr, and Lyn as well as Flt3 bearing an activating internal tandem duplication (ITD). Flt3-ITD expression sensitized human TF-1 myeloid cells to growth arrest by A-419259, supporting direct action on the Flt3-ITD kinase domain. Cells transformed with the Flt3-ITD mutants D835Y and F691L were resistant to A-419259, while co-expression of Hck or Fgr restored inhibitor sensitivity to Flt3-ITD D835Y. Conversely, Hck and Fgr mutants with engineered A-419259 resistance mutations decreased sensitivity of TF-1/Flt3-ITD cells. To investigate de novo resistance mechanisms, A-419259-resistant Flt3-ITD+ AML cell populations were derived via long-term dose escalation. Whole exome sequencing identified a distinct Flt3-ITD kinase domain mutation (N676S/T) among all A-419259 target kinases in each of six independent resistant cell populations. These studies show that Hck and Fgr expression influences inhibitor sensitivity and the pathway to acquired resistance in Flt3-ITD+ AML.

Klíčová slova:

Acute myeloid leukemia – Bone marrow cells – Cell viability testing – In vitro kinase assay – Kinase inhibitors – Point mutation – Regression analysis – Tyrosine kinases


Zdroje

1. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68: 7–30. doi: 10.3322/caac.21442 29313949

2. Lichtman MA (2013) A historical perspective on the development of the cytarabine (7days) and daunorubicin (3days) treatment regimen for acute myelogenous leukemia: 2013 the 40th anniversary of 7+3. Blood Cells Mol Dis 50: 119–130. doi: 10.1016/j.bcmd.2012.10.005 23154039

3. Birg F, Courcoul M, Rosnet O, Bardin F, Pebusque MJ, Marchetto S et al. (1992) Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood 80: 2584–2593. 1384791

4. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99: 4326–4335. doi: 10.1182/blood.v99.12.4326 12036858

5. Parcells BW, Ikeda AK, Simms-Waldrip T, Moore TB, Sakamoto KM (2006) FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. Stem Cells 24: 1174–1184. doi: 10.1634/stemcells.2005-0519 16410383

6. Janke H, Pastore F, Schumacher D, Herold T, Hopfner KP, Schneider S et al. (2014) Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia. PLoS One 9: e89560. doi: 10.1371/journal.pone.0089560 24608088

7. Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ et al. (2012) Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485: 260–263. doi: 10.1038/nature11016 22504184

8. Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F et al. (2004) The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 13: 169–178. doi: 10.1016/s1097-2765(03)00505-7 14759363

9. Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL et al. (2018) Functional genomic landscape of acute myeloid leukaemia. Nature 562: 526–531. doi: 10.1038/s41586-018-0623-z 30333627

10. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98: 1752–1759. doi: 10.1182/blood.v98.6.1752 11535508

11. Wander SA, Levis MJ, Fathi AT (2014) The evolving role of FLT3 inhibitors in acute myeloid leukemia: quizartinib and beyond. Ther Adv Hematol 5: 65–77. doi: 10.1177/2040620714532123 24883179

12. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD et al. (2017) Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med 377: 454–464. doi: 10.1056/NEJMoa1614359 28644114

13. Weis TM, Marini BL, Bixby DL, Perissinotti AJ (2019) Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia. Crit Rev Oncol Hematol 141: 125–138. doi: 10.1016/j.critrevonc.2019.06.011 31279288

14. Sudhindra A, Smith CC (2014) FLT3 inhibitors in AML: are we there yet? Curr Hematol Malig Rep 9: 174–185. doi: 10.1007/s11899-014-0203-8 24682858

15. Smith CC, Zhang C, Lin KC, Lasater EA, Zhang Y, Massi E et al. (2015) Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397. Cancer Discov 5: 668–679. doi: 10.1158/2159-8290.CD-15-0060 25847190

16. Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH et al. (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: 293–300. doi: 10.1182/blood-2005-06-2469 16150941

17. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. (2009) AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 114: 2984–2992. doi: 10.1182/blood-2009-05-222034 19654408

18. Dos SC, Demur C, Bardet V, Prade-Houdellier N, Payrastre B, Recher C (2008) A critical role for Lyn in acute myeloid leukemia. Blood 111: 2269–2279. doi: 10.1182/blood-2007-04-082099 18056483

19. Dos Santos C., McDonald T, Ho YW, Liu H, Lin A, Forman SJ et al. (2013) The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents. Blood 122: 1900–1913. doi: 10.1182/blood-2012-11-466425 23896410

20. Weir MC, Shu ST, Patel RK, Hellwig S, Chen L, Tan L et al. (2018) Selective inhibition of the myeloid Src-family kinase Fgr potently suppresses AML cell growth in vitro and in vivo. ACS Chem Biol 13: 1551–1559. doi: 10.1021/acschembio.8b00154 29763550

21. Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S et al. (2010) Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med 2: 17ra9.

22. Saito Y, Yuki H, Kuratani M, Hashizume Y, Takagi S, Honma T et al. (2013) A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo. Sci Transl Med 5: 181ra52.

23. Koda Y, Kikuzato K, Mikuni J, Tanaka A, Yuki H, Honma T et al. (2017) Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors. Bioorg Med Chem Lett 27: 4994–4998. doi: 10.1016/j.bmcl.2017.10.012 29037944

24. Shen K, Moroco JA, Patel RK, Shi H, Engen JR, Dorman HR et al. (2018) The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation. Sci Signal 11: eaat5916.

25. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT et al. (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26: 127–132. doi: 10.1038/nbt1358 18183025

26. Rodems SM, Hamman BD, Lin C, Zhao J, Shah S, Heidary D et al. (2002) A FRET-based assay platform for ultra-high density drug screening of protein kinases and phosphatases. Assay Drug Dev Technol 1: 9–19. doi: 10.1089/154065802761001266 15090152

27. Hellwig S, Miduturu CV, Kanda S, Zhang J, Filippakopoulos P, Salah E et al. (2012) Small-molecule inhibitors of the c-Fes protein-tyrosine kinase. Chem Biol 19: 529–540. doi: 10.1016/j.chembiol.2012.01.020 22520759

28. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del AG, Levy-Moonshine A et al. (2013) From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics 43: 11–33. doi: 10.1002/0471250953.bi1110s43 25431634

29. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30: 2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

30. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20: 1297–1303. doi: 10.1101/gr.107524.110 20644199

31. Cingolani P, Platts A, Wang IL, Coon M, Nguyen T, Wang L et al. (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6: 80–92.

32. Wong WC, Kim D, Carter H, Diekhans M, Ryan MC, Karchin R (2011) CHASM and SNVBox: toolkit for detecting biologically important single nucleotide mutations in cancer. Bioinformatics 27: 2147–2148. doi: 10.1093/bioinformatics/btr357 21685053

33. Kitamura T, Tange T, Terasawa T, Chiba S, Kuwaki T, Miyagawa K et al. (1989) Establishment and characterization of a unique human cell line that proliferates dependently on GM-CSF, IL-3 or erythropoietin. J Cell Physiol 140: 323–334. doi: 10.1002/jcp.1041400219 2663885

34. Weir MC, Hellwig S, Tan L, Liu Y, Gray NS, Smithgall TE (2017) Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth. PLoS One 12: e0181178. doi: 10.1371/journal.pone.0181178 28727840

35. Parker LJ, Taruya S, Tsuganezawa K, Ogawa N, Mikuni J, Honda K et al. (2014) Kinase crystal identification and ATP-competitive inhibitor screening using the fluorescent ligand SKF86002. Acta Crystallogr D Biol Crystallogr 70: 392–404. doi: 10.1107/S1399004713028654 24531473

36. Pene-Dumitrescu T, Peterson LF, Donato NJ, Smithgall TE (2008) An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259. Oncogene 27: 7055–7069. doi: 10.1038/onc.2008.330 18794796

37. Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S et al. (2014) SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 25: 226–242. doi: 10.1016/j.ccr.2014.01.022 24525236

38. Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D et al. (2012) Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther 340: 350–359. doi: 10.1124/jpet.111.188441 22040680

39. von BN, Engh RA, Aberg E, Sanger J, Peschel C, Duyster J (2009) FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res 69: 3032–3041. doi: 10.1158/0008-5472.CAN-08-2923 19318574

40. Yuan X, Chen Y, Zhang W, He J, Lei L, Tang M et al. (2019) Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia. J Med Chem 62: 4158–4173. doi: 10.1021/acs.jmedchem.9b00223 30939008


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