BTK inhibition sensitizes acute lymphoblastic leukemia to asparaginase by suppressing the amino acid response pathway
Miriam Butler, Dorette S van Ingen Schenau, Jiangyan Yu, Silvia Jenni, Maria P Dobay, Rico Hagelaar, Britt M T Vervoort, Trisha M Tee, Fieke W Hoff, Jules P Meijerink, Steven M Kornblau, Beat Bornhauser, Jean-Pierre Bourquin, Roland P Kuiper, Laurens T van der Meer, Frank N van Leeuwen, Miriam Butler, Dorette S van Ingen Schenau, Jiangyan Yu, Silvia Jenni, Maria P Dobay, Rico Hagelaar, Britt M T Vervoort, Trisha M Tee, Fieke W Hoff, Jules P Meijerink, Steven M Kornblau, Beat Bornhauser, Jean-Pierre Bourquin, Roland P Kuiper, Laurens T van der Meer, Frank N van Leeuwen
Abstract
Asparaginase (ASNase) therapy has been a mainstay of acute lymphoblastic leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we used a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's tyrosine kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc-mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient-derived xenografts, regardless of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL. This trial was registered at www.clinicaltrials.gov as # NCT02884453.
© 2021 by The American Society of Hematology.
Figures
References
- Pieters R, Hunger SP, Boos J, et al. . L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. 2011;117(2):238-249.
- Covini D, Tardito S, Bussolati O, et al. . Expanding targets for a metabolic therapy of cancer: L-asparaginase. Recent Patents Anticancer Drug Discov. 2012;7(1):4-13.
- Fernandes HS, Silva Teixeira CS, Fernandes PA, Ramos MJ, Cerqueira NM. Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections. Expert Opin Ther Pat. 2017;27(3):283-297.
- Tong WH, Pieters R, Kaspers GJ, et al. . A prospective study on drug monitoring of PEG-asparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 2014;123(13):2026-2033.
- Henriksen LT, Nersting J, Raja RA, et al. ; Nordic Society of Paediatric Haematology and Oncology (NOPHO) group . Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia. Br J Haematol. 2014;166(2):213-220.
- Rizzari C, Lanvers-Kaminsky C, Valsecchi MG, et al. . Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study. Haematologica. 2019;104(9):1812-1821.
- Iwamoto S, Mihara K, Downing JR, Pui CH, Campana D. Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest. 2007; 117(4):1049-1057.
- Wang T, Wei JJ, Sabatini DM, Lander ES. Genetic screens in human cells using the CRISPR-Cas9 system. Science. 2014; 343(6166):80-84.
- Li W, Xu H, Xiao T, et al. . MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15(12):554.
- Schmitz M, Breithaupt P, Scheidegger N, et al. . Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment. Blood. 2011;118(7):1854-1864.
- Frismantas V, Dobay MP, Rinaldi A, et al. . Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood. 2017;129(11):e26-e37.
- Ianevski A, He L, Aittokallio T, Tang J. SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics. 2017;33(15):2413-2415.
- Li J, Zhao W, Akbani R, et al. . Characterization of human cancer cell lines by reverse-phase protein arrays. Cancer Cell. 2017;31(2):225-239.
- Tibes R, Qiu Y, Lu Y, et al. . 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. 2006;5(10):2512-2521.
- Lin G, Chai J, Yuan S, et al. . VennPainter: a tool for the comparison and identification of candidate genes based on Venn diagrams. PLoS One. 2016;11(4):e0154315.
- Szklarczyk D, Gable AL, Lyon D, et al. . STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607-D613.
- Krämer A, Green J, Pollard J Jr, Tugendreich S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 2014;30(4):523-530.
- Wortel IMN, van der Meer LT, Kilberg MS, van Leeuwen FN. Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends Endocrinol Metab. 2017;28(11):794-806.
- Donnelly N, Gorman AM, Gupta S, Samali A. The eIF2α kinases: their structures and functions. Cell Mol Life Sci. 2013;70(19):3493-3511.
- Leprivier G, Remke M, Rotblat B, et al. . The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell. 2013;153(5):1064-1079.
- Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001;20(16):4370-4379.
- Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 2005;24(6):1243-1255.
- Lien EC, Dibble CC, Toker A. PI3K signaling in cancer: beyond AKT. Curr Opin Cell Biol. 2017;45:62-71.
- Campbell R, Chong G, Hawkes EA. Novel indications for Bruton’s tyrosine kinase inhibitors, beyond hematological malignancies. J Clin Med. 2018;7(4):E62.
- Kim HO. Development of BTK inhibitors for the treatment of B-cell malignancies. Arch Pharm Res. 2019;42(2):171-181.
- Nguyen HA, Su Y, Zhang JY, et al. . A novel l-asparaginase with low l-glutaminase coactivity is highly efficacious against both T- and B-cell acute lymphoblastic leukemias in vivo. Cancer Res. 2018;78(6):1549-1560.
- Tameire F, Verginadis II, Leli NM, et al. . ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression [published correction appears in Nat Cell Biol. 2019;21:1052]. Nat Cell Biol. 2019;21(7):889-899.
- Yeomans A, Thirdborough SM, Valle-Argos B, et al. . Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation. Blood. 2016;127(4):449-457.
- Pede V, Rombout A, Vermeire J, et al. . CLL cells respond to B-cell receptor stimulation with a microRNA/mRNA signature associated with MYC activation and cell cycle progression [published correction appears in PLoS One. 2014;9(1):10.1371]. PLoS One. 2013; 8(4):e60275.
- Moyo TK, Wilson CS, Moore DJ, Eischen CM. Myc enhances B-cell receptor signaling in precancerous B cells and confers resistance to BTK inhibition. Oncogene. 2017;36(32):4653-4661.
- Lee J, Zhang LL, Wu W, et al. . Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma. Blood Adv. 2018;2(16):2039-2051.
- Chong IY, Aronson L, Bryant H, et al. . Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer. Gut. 2018;67(10):1780-1792.
- Davidson M, Chong IY-S, Cunningham D, et al. . iMYC: proof-of-concept study of ibrutinib in c-MYC and HER2 amplified oesophagogastric carcinoma. J Clin Oncol. 2017;35(4 suppl):TPS221.
- Delmore JE, Issa GC, Lemieux ME, et al. . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
- Nakamura A, Nambu T, Ebara S, et al. . Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response. Proc Natl Acad Sci USA. 2018;115(33):E7776-E7785.
- Wilson GJ, Bunpo P, Cundiff JK, Wek RC, Anthony TG. The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment. Am J Physiol Endocrinol Metab. 2013;305(9):E1124-E1133.
- Phillipson-Weiner L, Mirek ET, Wang Y, McAuliffe WG, Wek RC, Anthony TG. General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2016;310(11):G1061-G1070.
- Kim E, Hurtz C, Koehrer S, et al. . Ibrutinib inhibits pre-BCR+ B-cell acute lymphoblastic leukemia progression by targeting BTK and BLK. Blood. 2017;129(9):1155-1165.
- Weber ANR, Bittner Z, Liu X, Dang TM, Radsak MP, Brunner C. Bruton’s tyrosine kinase: an emerging key player in innate immunity. Front Immunol. 2017;8:1454.
- Woo MH, Hak LJ, Storm MC, et al. . Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia. J Clin Oncol. 1999;17(5):1568-1573.
- Goldwirt L, Beccaria K, Ple A, Sauvageon H, Mourah S. Ibrutinib brain distribution: a preclinical study. Cancer Chemother Pharmacol. 2018;81(4):783-789.
- Cabannes-Hamy A, Lemal R, Goldwirt L, et al. . Efficacy of ibrutinib in the treatment of Bing-Neel syndrome. Am J Hematol. 2016;91(3):E17-E19.
- Bernard S, Goldwirt L, Amorim S, et al. . Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood. 2015;126(14):1695-1698.
- Herman SE, Mustafa RZ, Jones J, Wong DH, Farooqui M, Wiestner A. Treatment with ibrutinib inhibits BTK- and VLA-4-dependent adhesion of chronic lymphocytic leukemia cells in vivo. Clin Cancer Res. 2015;21(20):4642-4651.
- Regan JA, Cao Y, Dispenza MC, et al. . Ibrutinib, a Bruton’s tyrosine kinase inhibitor used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and basophil activation test reactivity. J Allergy Clin Immunol. 2017;140(3):875-879.e1.
- Eifert C, Wang X, Kokabee L, et al. . A novel isoform of the B cell tyrosine kinase BTK protects breast cancer cells from apoptosis. Genes Chromosomes Cancer. 2013;52(10):961-975.
- Li T, Deng Y, Shi Y, et al. . Bruton’s tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma. Oncogene. 2018;37(47):6180-6194.
Source: PubMed