High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

Blood

Volumn 128, Issue 7, 2016, Pages 934-947

  Oppermann, Sina ^a   Ylanko, Jarkko ^a   Shi, Yonghong ^a   Hariharan, Santosh ^a   Oakes, Christopher C ^b   Brauer, Patrick M ^c   Zúñiga Pflücker, Juan C ^a,c   Leber, Brian ^d   Spaner, David E ^a,c,e   Andrews, David W ^a,c,e  

^a UNIVERSITY OF TORONTO   (Canada)

^b THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

^c UNIVERSITY OF TORONTO   (Canada)

^d MCMASTER UNIVERSITY   (Canada)

^e DEPARTMENT OF RADIATION ONCOLOGY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

A 1210477; A1 PROTEIN; ANTILEUKEMIC AGENT; BH3 PROTEIN; BIM PROTEIN; CYTOCHROME C; ENDONUCLEASE G; IBRUTINIB; IDELALISIB; NAVITOCLAX; PEPTIDES AND PROTEINS; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN INHIBITOR; PROTEIN MCL 1; SECOND MITOCHONDRIAL ACTIVATOR OF CASPASE; STAUROSPORINE; SUNITINIB; UNCLASSIFIED DRUG; VENETOCLAX; FUSED HETEROCYCLIC RINGS; INDOLE DERIVATIVE; PROTEIN BCL X; PROTEIN KINASE INHIBITOR; PURINE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; PYRROLE DERIVATIVE; QUINAZOLINONE DERIVATIVE; SULFONAMIDE;

ADULT; AGED; APOPTOSIS; ARTICLE; BONE MARROW STROMA CELL; CANCER PATIENT; CANCER RESISTANCE; CHEMOSENSITIVITY; CHRONIC LYMPHATIC LEUKEMIA; COCULTURE; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOWN REGULATION; DRUG EFFICACY; DRUG POTENTIATION; FEMALE; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IMMUNOGLOBULIN VARIABLE REGION; IN VITRO STUDY; LEUKEMIA CELL; MALE; MIDDLE AGED; PERSONALIZED MEDICINE; PRIMARY CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; UPREGULATION; VERY ELDERLY; DOSE RESPONSE; DRUG EFFECTS; DRUG RESISTANCE; GENETICS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; METABOLISM; MUTATION; PATHOLOGY; PRECLINICAL STUDY; REPRODUCIBILITY; STROMA CELL; THREE DIMENSIONAL IMAGING;

BCL-X PROTEIN; BRIDGED BICYCLO COMPOUNDS, HETEROCYCLIC; CELLULAR MICROENVIRONMENT; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; DRUG RESISTANCE, NEOPLASM; HUMANS; IMAGING, THREE-DIMENSIONAL; INDOLES; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MUTATION; PROTEIN KINASE INHIBITORS; PURINES; PYRAZOLES; PYRIMIDINES; PYRROLES; QUINAZOLINONES; REPRODUCIBILITY OF RESULTS; SIGNAL TRANSDUCTION; STROMAL CELLS; SULFONAMIDES; UP-REGULATION;

EID: 84993949727     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2015-12-687814     Document Type: Article

References (78)

1. Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res. 2008;14(9):2519-2526.
2. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood. 2000;96(8):2655-2663.
3. Kurtova AV, Balakrishnan K, Chen R, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114(20):4441-4450.
4. Vogler M, Butterworth M, Majid A, et al. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood. 2009;113(18):4403-4413.
5. Brahmbhatt H, Oppermann S, Osterlund EJ, Leber B, Andrews DW. Molecular pathways: leveraging the BCL-2 interactome to kill cancer cells-mitochondrial outer membrane permeabilization and beyond. Clin Cancer Res. 2015;21(12):2671-2676.
6. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2 [published correction appears in Proc Natl Acad Sci USA. 2006;103(7):2464]. Proc Natl Acad Sci USA. 2005;102(39):13944-13949.
7. Smit LA, Hallaert DY, Spijker R, et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood. 2007;109(4):1660-1668.
8. Anderson MA, Deng J, Seymour JF, et al. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism. Blood. 2016;127(25):3215-3224.
9. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322.
10. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.
11. Crystal AS, Shaw AT, Sequist LV, et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. 2014;346(6216):1480-1486.
12. Spaner DE, Lee E, Shi Y, et al. PPAR-alpha is a therapeutic target for chronic lymphocytic leukemia. Leukemia. 2013;27(5):1090-1099.
13. Tomic J, White D, Shi Y, et al. Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity. J Immunol. 2006;176(6):3830-3839.
14. Spaner DE, Shi Y, White D, et al. Immunomodulatory effects of Toll-like receptor-7 activation on chronic lymphocytic leukemia cells. Leukemia. 2006;20(2):286-295.
15. Shen M, Zhang Y, Saba N, Austin CP, Wiestner A, Auld DS. Identification of therapeutic candidates for chronic lymphocytic leukemia from a library of approved drugs [published correction appears at http://dx.doi.org/10.1371/annotation/e2536fcb-3ab3-44a0-8eab-91aaeb8e49b6]. PLoS One. 2013;8(9):e75252.
16. Thijssen R, Slinger E, Weller K, et al. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015;100(8):e302-e306.
17. Crassini K, Stevenson WS, Mulligan SP, Best OG. The MEK1/2 inhibitor, MEKi-1, induces cell death in chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment and is synergistic with fludarabine. Leuk Lymphoma. 2015;56(12):3407-3417.
18. Crassini K, Mulligan SP, Best OG. Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: a review of the in vitro and clinical trials to date. World J Clin Cases. 2015;3(8):694-704.
19. Li Y, Shi Y, McCaw L, et al. Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A. Blood. 2015;126(6):766-778.
20. Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008;7(12):989-1000.
21. Galluzzi L, Bravo-San Pedro JM, Vitale I, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2015;22(1):58-73.
22. Kepp O, Galluzzi L, Lipinski M, Yuan J, Kroemer G. Cell death assays for drug discovery. Nat Rev Drug Discov. 2011;10(3):221-237.
23. Collins TJ, Ylanko J, Geng F, Andrews DW. A versatile cell death screening assay using dyestained cells and multivariate image analysis. Assay Drug Dev Technol. 2015;13(9):547-557.
24. Douglas RS, Capocasale RJ, Lamb RJ, Nowell PC, Moore JS. Chronic lymphocytic leukemia B cells are resistant to the apoptotic effects of transforming growth factor-beta. Blood. 1997;89(3):941-947.
25. Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701-738.
26. Panayiotidis P, Ganeshaguru K, Jabbar SA, Hoffbrand AV. Interleukin-4 inhibits apoptotic cell death and loss of the bcl-2 protein in B-chronic lymphocytic leukaemia cells in vitro. Br J Haematol. 1993;85(3):439-445.
27. Steele AJ, Prentice AG, Cwynarski K, et al. The JAK3-selective inhibitor PF-956980 reverses the resistance to cytotoxic agents induced by interleukin-4 treatment of chronic lymphocytic leukemia cells: potential for reversal of cytoprotection by the microenvironment. Blood. 2010;116(22):4569-4577.
28. de Totero D, Reato G, Mauro F, et al. IL4 production and increased CD30 expression by a unique CD8+ T-cell subset in B-cell chronic lymphocytic leukaemia. Br J Haematol. 1999;104(3):589-599.
29. Kay NE, Han L, Bone N, Williams G. Interleukin 4 content in chronic lymphocytic leukaemia (CLL) B cells and blood CD8+ T cells from B-CLL patients: impact on clonal B-cell apoptosis. Br J Haematol. 2001;112(3):760-767.
30. Rossmann ED, Lewin N, Jeddi-Tehrani M, Osterborg A, Mellstedt H. Intracellular T cell cytokines in patients with B cell chronic lymphocytic leukaemia (B-CLL). Eur J Haematol. 2002;68(5):299-306.
31. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884-896.
32. Christensen JG. A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann Oncol. 2007;18(suppl 10):x3-x10.
33. Davis MI, Hunt JP, Herrgard S, et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011;29(11):1046-1051.
34. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci USA. 2007;104(43):17069-17074.
35. Henderson VC, Demko N, Hakala A, et al. A meta-analysis of threats to valid clinical inference in preclinical research of sunitinib. eLife. 2015;4:e08351.
36. Shanafelt T, Zent C, Byrd J, et al. Phase II trials of single-agent anti-VEGF therapy for patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2010;51(12):2222-2229.
37. Claus R, Wilop S, Hielscher T, et al. A systematic comparison of quantitative high-resolution DNA methylation analysis and methylation-specific PCR. Epigenetics. 2012;7(7):772-780.
38. Kröber A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100(4):1410-1416.
39. Mertens D, Stilgenbauer S. Prognostic and predictive factors in patients with chronic lymphocytic leukemia: relevant in the era of novel treatment approaches? J Clin Oncol. 2014;32(9):869-872.
40. Oakes CC, Seifert M, Assenov Y, et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet. 2016;48(3):253-264.
41. Queirós AC, Villamor N, Clot G, et al. A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact. Leukemia. 2015;29(3):598-605.
42. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood. 2008;111(2):846-855.
43. Purroy N, Abrisqueta P, Carabia J, et al. Targeting the proliferative and chemoresistant compartment in chronic lymphocytic leukemia by inhibiting survivin protein. Leukemia. 2014;28(10):1993-2004.
44. Néron S, Pelletier A, Chevrier MC, Monier G, Lemieux R, Darveau A. Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand. Immunol Invest. 1996;25(1-2):79-89.
45. Soderquist R, Bates DJ, Danilov AV, Eastman A. Gossypol overcomes stroma-mediated resistance to the BCL2 inhibitor ABT-737 in chronic lymphocytic leukemia cells ex vivo. Leukemia. 2013;27(11):2262-2264.
46. Willimott S, Baou M, Naresh K, Wagner SD. CD154 induces a switch in pro-survival Bcl-2 family members in chronic lymphocytic leukaemia. Br J Haematol. 2007;138(6):721-732.
47. Willimott S, Baou M, Huf S, Deaglio S, Wagner SD. Regulation of CD38 in proliferating chronic lymphocytic leukemia cells stimulated with CD154 and interleukin-4. Haematologica. 2007;92(10):1359-1366.
48. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397.
49. Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119(5):1182-1189.
50. Woyach JA, Johnson AJ. Targeted therapies in CLL: mechanisms of resistance and strategies for management. Blood. 2015;126(4):471-477.
51. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007;117(1):112-121.
52. Tromp JM, Tonino SH, Elias JA, et al. Dichotomy in NF-kappaB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering. Oncogene. 2010;29(36):5071-5082.
53. Davids MS, Brown JR. Targeting the B cell receptor pathway in chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(12):2362-2370.
54. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563-574.
55. Rahmani M, Aust MM, Attkisson E, Williams DC Jr, Ferreira-Gonzalez A, Grant S. Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process. Blood. 2012;119(25):6089-6098.
56. Abrams TJ, Murray LJ, Pesenti E, et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther. 2003;2(10):1011-1021.
57. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2(5):471-478.
58. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9(1):327-337.
59. Murray LJ, Abrams TJ, Long KR, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis. 2003;20(8):757-766.
60. O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101(9):3597-3605.
61. Debrincat MA, Pleines I, Lebois M, et al. BCL-2 is dispensable for thrombopoiesis and platelet survival. Cell Death Dis. 2015;6:e1721.
62. Kaefer A, Yang J, Noertersheuser P, et al. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother Pharmacol. 2014;74(3):593-602.
63. Leverson JD, Phillips DC, Mitten MJ, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015;7(279):279ra40.
64. Roberts AW, Seymour JF, Brown JR, et al. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012;30(5):488-496.
65. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705-3715.
66. O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58.
67. Martinez Marignac VL, Smith S, Toban N, Bazile M, Aloyz R. Resistance to dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic reprogramming. Oncotarget. 2013;4(12):2550-2566.
68. Pitini VV. The role of p53 and autophagy in dasatinib resistance of CLL lymphocytes. Leuk Res. 2011;35(1):32-33.
69. Amrein PC. The potential for dasatinib in treating chronic lymphocytic leukemia, acute myeloid leukemia, and myeloproliferative neoplasms. Leuk Lymphoma. 2011;52(5):754-763.
70. Amrein PC, Attar EC, Takvorian T, et al. Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia. Clin Cancer Res. 2011;17(9):2977-2986.
71. Eley T, Luo FR, Agrawal S, et al. Phase I study of the effect of gastric acid pH modulators on the bioavailability of oral dasatinib in healthy subjects. J Clin Pharmacol. 2009;49(6):700-709.
72. Hussain SR, Lucas DM, Johnson AJ, et al. Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium. Blood. 2008;111(6):3190-3199.
73. Lin TS. Novel agents in chronic lymphocytic leukemia: efficacy and tolerability of new therapies. Clin Lymphoma Myeloma. 2008;8(suppl 4):S137-S143.
74. Lanasa MC, Andritsos L, Brown JR, et al. Final results of EFC6663: a multicenter, international, phase 2 study of alvocidib for patients with fludarabine-refractory chronic lymphocytic leukemia. Leuk Res. 2015;39(5):495-500.
75. Goodman VL, Rock EP, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13(5):1367-1373.
76. Kronabel D. Possible influence of some foods on the metabolism of ibrutinib. Clin Lab. 2015;61(3-4):443-444.
77. Rais R, Zhao M, He P, Xu L, Deeken JF, Rudek MA. Quantitation of unbound sunitinib and its metabolite N-desethyl sunitinib (SU12662) in human plasma by equilibrium dialysis and liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. Biomed Chromatogr. 2012;26(11):1315-1324.
78. Weiss J, Gajek T, Köhler BC, Haefeli WE. Venetoclax (ABT-199) might act as a perpetrator in pharmacokinetic drug-drug interactions. Pharmaceutics. 2016;8(1).