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M. Boudny et al.
resting B cells are vulnerable to CHK1 depletion.22
The MU380 single-agent activity is noteworthy, espe- cially in the light of the fact that CLL is typically resistant to therapy based on a single drug and that most current therapeutic regimens consist of several agents with com- bined mechanisms of action. In any case, it will be worth- while analyzing potential synergy between CHK1 inhibi- tion and current state-of-the-art CLL therapeutics target- ing BCR signaling or BCL2 protein. Such analysis was not within the scope of this pilot study, but preliminary data we obtained with MEC-1 cells indicate an approximate additive effect of MU380 combined with ibrutinib (Boudny et al., 2019, unpublished observation). Furthermore, a recent study focusing on molecular analysis of druggable path- ways in blood cancers49 determined that the CLL cell response to SCH900776 is distinct from that of BCR path- way inhibitors. Concerning BCL2, at least the total level of this protein is unaffected by MU380. It might, therefore, be interesting to test a combination of MU380 with BH3- mimetics, e.g. venetoclax. Since MU380 reduces impor- tant anti-apoptotic proteins MCL1 and NF-κB activated by
BCR signaling in CLL cells,43,50 response to combination treatment could, indeed, be synergistic.
In summary, we have demonstrated that our novel CHK1 inhibitor MU380 effectively affects both dividing and non-dividing CLL cells harboring TP53 mutations. Consequently, CHK1 inhibition may represent an attrac- tive therapeutic option for high-risk CLL.
Funding
The work was supported by Grant n. 15-33999A provided by the Ministry of Health of the Czech Republic, Project FNBr 65269705 – Conceptual Development of Research Organization, Project MUNI/A/1105/2018, Project
CZ-OPENSCREEN: National Infrastructure for Chemical Biology (Identification code: LM2015063), and by the National Program of Sustainability II (project No. LQ1605) and CEITEC 2020 Project (LQ1601) provided by the Ministry of Education, Youth and Sports of the Czech Republic. We thank Veronika Sandova for advice with transfection experiments and Olga Stehlikova for help with flow cytometry. We thank Richard Zimmerman for his English editing.
References
1. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in nor- mal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
2. Thompson PA, Burger JA. Bruton’s tyrosine kinase inhibitors: first and second generation agents for patients with Chronic Lymphocytic Leukemia (CLL). Expert Opin Investig Drugs. 2018;27(1):31-42.
3. Daniel C, Mato AR. BCL-2 as a therapeutic target in chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2017;15(3):210-218.
4. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib- treated patients in the United States: a real- world analysis. Haematologica. 2018;103(5): 874-879.
5. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol. 2015;1(1): 80-87.
6. O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919.
7. Jones J, Mato A, Coutre S, et al. Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials. Br J Haematol. 2018;182(4):504-512.
8. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247- 3254.
9. Thompson R, Eastman A. The cancer thera- peutic potential of Chk1 inhibitors: how mechanistic studies impact on clinical trial design: Therapeutic potential of Chk1 inhibitors. Br J Clin Pharmacol. 2013;76 (3):358-369.
10. González Besteiro MA, Gottifredi V. The fork and the kinase: a DNA replication tale
from a CHK1 perspective. Mutat Res Rev.
2015;763168-180.
11. Bartkova J, Horejsí Z, Koed K, et al. DNA
damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434(7035):864-870.
12. de Klein A, Muijtjens M, van Os R, et al. Targeted disruption of the cell-cycle check- point gene ATR leads to early embryonic lethality in mice. Curr Biol. 2000;10(8):479- 482.
13. Takai H, Tominaga K, Motoyama N, et al. Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice. Genes Dev. 2000;14(12):1439-1447.
14. Bryant C, Rawlinson R, Massey AJ. Chk1 inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers. BMC Cancer. 2014;14:570.
15. Sen T, Tong P, Stewart CA, et al. CHK1 Inhibition in Small-Cell Lung Cancer Produces Single-Agent Activity in Biomarker-Defined Disease Subsets and Combination Activity with Cisplatin or Olaparib. Cancer Res. 2017;77(14):3870- 3884.
16. Manic G, Signore M, Sistigu A, et al. CHK1- targeted therapy to deplete DNA replica- tion-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. Gut. 2018;67(5):903-917.
17. Lowery CD, VanWye AB, Dowless M, et al. The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma. Clin Cancer Res. 2017;23(15):4354-4363.
18. Oo ZY, Stevenson AJ, Proctor M, et al. Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo. Clin Cancer Res. 2018;24(12):2901- 2912.
19. Walton MI, Eve PD, Hayes A, et al. The clin- ical development candidate CCT245737 is an orally active CHK1 inhibitor with preclin- ical activity in RAS mutant NSCLC and Eμ- MYC driven B-cell lymphoma. Oncotarget. 2016;7(3):2329-2342.
20. Bryant C, Scriven K, Massey AJ. Inhibition
of the checkpoint kinase Chk1 induces DNA damage and cell death in human Leukemia and Lymphoma cells. Mol Cancer. 2014;13:147.
21. Iacobucci I, Di Rorà AGL, Falzacappa MVV, et al. In vitro and in vivo single-agent effica- cy of checkpoint kinase inhibition in acute lymphoblastic leukemia. J Hematol Oncol. 2015;8:125.
22. Schuler F, Weiss JG, Lindner SE, et al. Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis. Nat Commun. 2017;8(1):1697.
23. Kwok M, Davies N, Agathanggelou A, et al. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood. 2016;127(5):582-595.
24. Zemanova J, Hylse O, Collakova J, et al. Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53- mutated B-lymphoid cells. Oncotarget. 2016;7(38):62091-62106.
25. Guzi TJ, Paruch K, Dwyer MP, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011;10(4):591-602.
26. Samadder P, Suchánková T, Hylse O, et al. Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyra- zole Pharmacophore Resistant to Metabolic N-dealkylation. Mol Cancer Ther. 2017;16 (9):1831-1842.
27. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28(6):622-629.
28. Patten PEM, Chu CC, Albesiano E, et al. IGHV-unmutated and IGHV-mutated chron- ic lymphocytic leukemia cells produce acti- vation-induced deaminase protein with a full range of biologic functions. Blood. 2012;120(24):4802-4811.
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