Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Review

The cell cycle checkpoint inhibitors in the treatment of leukemias

Authors: A. Ghelli Luserna di Rora’, I. Iacobucci, G. Martinelli

Published in: Journal of Hematology & Oncology | Issue 1/2017

Login to get access

Abstract

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.
Literature
1.
2.
Karanjawala ZE, Murphy N, Hinton DR, Hsieh CL, Lieber MR. Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in DNA double-strand break repair mutants. Curr Biol. 2002;12:397–402.PubMedCrossRef
3.
Sallmyr A, Fan J, Rassool FV. Genomic instability in myeloid malignancies: increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair. Cancer Lett. 2008;1–9.
4.
Velic D, Couturier A, Ferreira M, Rodrigue A, Poirier G, Fleury F, Masson J-Y. DNA damage signalling and repair inhibitors: the long-sought-after Achilles’ heel of cancer. Biomolecules. 2015;5:3204–59.PubMedPubMedCentralCrossRef
5.
Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14:197–210.CrossRef
6.
Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005;434:605–11.PubMedCrossRef
7.
Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 2003;22:5612–21.PubMedPubMedCentralCrossRef
8.
Lamarche BJ, Orazio NI, Weitzman MD. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett. 2010;3682–3695.
9.
Girard P-M, Riballo E, Begg AC, Waugh A, Jeggo PA. Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. Oncogene. 2002;4191–9.
10.
Williams RS, Williams JS, Tainer JA, Williams RS, Williams JS, Tainer JA. Mre11–Rad50–Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol. 2007;85:509–20.PubMedCrossRef
11.
Williams RS, Moncalian G, Williams JS, Yamada Y, Limbo O, Shin DS, Groocock LM, Cahill D, Hitomi C, Guenther G, Moiani D, Carney JP, Russell P, Tainer JA. Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell. 2008;135:97–109.PubMedPubMedCentralCrossRef
12.
De Jager M, Van Noort J, Van Gent DC, Dekker C, Kanaar R, Wyman C. Human Rad50/Mre11 is a flexible complex that can tether DNA ends. Mol Cell. 2001;8:1129–35.PubMedCrossRef
13.
Lee J-H, Paull TT. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Sci (New York, NY). 2005;308:551–4.CrossRef
14.
15.
Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506.PubMedCrossRef
16.
Kozlov SV, Graham ME, Jakob B, Tobias F, Kijas AW, Tanuji M, Chen P, Robinson PJ, Taucher-Scholz G, Suzuki K, So S, Chen D, Lavin MF. Autophosphorylation and ATM activation: additional sites add to the complexity. J Biol Chem. 2011;286:9107–19.PubMedCrossRef
17.
Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003;300(June):1542–8.PubMedCrossRef
18.
Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 2005;19:1040–52.PubMedPubMedCentralCrossRef
19.
Weber AM, Ryan AJ. ATM and ATR as therapeutic targets in cancer. Pharmacol Ther. 2015;124–138.
20.
Liu S, Shiotani B, Lahiri M, Maréchal A, Tse A, Leung CCY, Glover JNM, Yang XH, Zou L. ATR autophosphorylation as a molecular switch for checkpoint activation. Mol Cell. 2011;43:192–202.PubMedPubMedCentralCrossRef
21.
Nam EA, Zhao R, Glick GG, Bansbach CE, Friedman DB, Cortez D. Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase. J Biol Chem. 2011;286:28707–14.PubMedPubMedCentralCrossRef
22.
Mordes DA, Cortez D. Activation of ATR and related PIKKs. Cell Cycle. 2008;2809–2812.
23.
Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O. ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J Exp Med. 2006;203:297–303.PubMedPubMedCentralCrossRef
24.
Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene. 2009;28:2925–39.PubMedCrossRef
25.
Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013;140:3079–93.PubMedCrossRef
26.
Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci. 1999;96:14973–7.PubMedPubMedCentralCrossRef
27.
Origanti S, Cai S, Munir AZ, White LS, Piwnica-Worms H. Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells. Oncogene. 2013;32(5):577–88.PubMedCrossRef
28.
Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003;421–429.
29.
30.
31.
Schmitt E, Boutros R, Froment C, Monsarrat B, Ducommun B, Dozier C. CHK1 phosphorylates CDC25B during the cell cycle in the absence of DNA damage. J Cell Sci. 2006;119(Pt 20):4269–75.PubMedCrossRef
32.
33.
34.
Watanabe N, Arai H, Iwasaki J-I, Shiina M, Ogata K, Hunter T, Osada H. Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Proc Natl Acad Sci U S A. 2005;102:11663–8.PubMedPubMedCentralCrossRef
35.
36.
Guardavaccaro D, Pagano M. Stabilizers and destabilizers controlling cell cycle oscillators. Mol Cell. 2006;1–4.
37.
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.PubMedCrossRef
38.
Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008;9:759–69.PubMedCrossRef
39.
Teive HA, Moro A, Moscovich M, Arruda WO, Munhoz RP, Raskin S, Ashizawa T. Ataxia-telangiectasia—a historical review and a proposal for a new designation: ATM syndrome. J Neurol Sci. 2015;355:3–6.PubMedPubMedCentralCrossRef
40.
Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–8.PubMedCrossRef
41.
Haidar MA, Kantarjian H, Manshouri T, Chang CY, O’Brien S, Freireich E, Keating M, Albitar M. ATM gene deletion in patients with adult acute lymphoblastic leukemia. Cancer. 2000;88:1057–62.PubMedCrossRef
42.
Network TCGAR. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.CrossRef
43.
Melo JV, Kumberova A, van Dijk AG, Goldman JM, Yuille MR. Investigation on the role of the ATM gene in chronic myeloid leukaemia. Leukemia. 2001;15:1448–50.PubMedCrossRef
44.
Takagi M, Sato M, Piao J, Miyamoto S, Isoda T, Kitagawa M, Honda H, Mizutani S. ATM-dependent DNA damage-response pathway as a determinant in chronic myelogenous leukemia. DNA Repair (Amst). 2013;12:500–7.CrossRef
45.
Starostik P, Manshouri T, Brien SO, Leukemia BCL, Lerner S, Keating M. Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia. Cancer Res. 1998;4552–4557.
46.
Puente XS, Beà S, Valdés-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, Munar M, Rubio-Pérez C, Jares P, Aymerich M, Baumann T, Beekman R, Belver L, Carrio A, Castellano G, Clot G, Colado E, Colomer D, Costa D, Delgado J, Enjuanes A, Estivill X, Ferrando AA, Gelpí JL, González B, González S, González M, Gut M, Hernández-Rivas JM, López-Guerra M, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519–24.PubMedCrossRef
47.
Jiang Y, Chen H-C, Su X, Thompson P, Liu X, Do K-A, Wierda W, Keating M, Plunkett W. ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2). Blood Cancer J. 2016;6:e465.
48.
49.
Dolnik A, Engelmann JC, Scharfenberger-schmeer M, Mauch J, Haldemann B, Fries T, Krönke J, Kühn MWM, Kayser S, Wolf S, Gaidzik VI, Schlenk RF, Rücker FG, Döhner H, Lottaz C, Döhner K, Bullinger L, Kelkenberg-schade S, Kro J, Ku MWM. Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin. Blood. 2013;120:83–93.CrossRef
50.
Offit K, Pierce H, Kirchhoff T, Kolachana P, Rapaport B, Gregersen P, Johnson S, Yossepowitch O, Huang H, Satagopan J, Robson M, Scheuer L, Nafa K, Ellis N. Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet. 2003;4:1.PubMedPubMedCentralCrossRef
51.
Thompson D, Seal S, Schutte M, McGuffog L, Barfoot R, Renwick A, Eeles R, Sodha N, Houlston R, Shanley S, Klijn J, Wasielewski M, Chang-Claude J, Futreal PA, Weber BL, Nathanson KL, Stratton M, Meijers-Heijboer H, Rahman N, Easton DF. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol Biomarkers Prev. 2006;15:2542–5.PubMedPubMedCentralCrossRef
52.
Hangaishi A, Ogawa S, Qiao Y, Wang L, Hosoya N, Yuji K, Imai Y, Takeuchi K, Miyawaki S, Hirai H. Neoplasms, mutations of Chk2 in primary hematopoietic. Blood. 2002;99:3075–8.PubMedCrossRef
53.
Hofmann WK, Miller CW, Tsukasaki K, Tavor S, Ikezoe T, Hoelzer D, Takeuchi S, Koeffler HP. Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias. Leuk Res. 2001;25:333–8.PubMedCrossRef
54.
Rudd MF, Sellick GS, Webb EL, Catovsky D, Houlston RS. Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Blood. 2006;108:638–44.PubMedCrossRef
55.
Bartkova J, Hamerlik P, Stockhausen M-T, Ehrmann J, Hlobilkova A, Laursen H, Kalita O, Kolar Z, Poulsen HS, Broholm H, Lukas J, Bartek J. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas. Oncogene. 2010;29:5095–102.PubMedCrossRef
56.
Halazonetis TD, Gorgoulis VG, Bartek J. An oncogene-induced DNA damage model for cancer development. Science. 2008;319:1352–5.PubMedCrossRef
57.
58.
De Klein A, Muijtjens M, Van Os R, Verhoeven Y, Smit B, Carr AM, Lehmann AR, Hoeijmakers JHJ. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr Biol. 2000;10:479–82.PubMedCrossRef
59.
Sawyers CL. Molecular consequences of the BCR-ABL translocation in chronic myelogenous leukemia. Leuk Lymphoma. 1993;11 Suppl 2:101–3.PubMedCrossRef
60.
Kim KT, Baird K, Davis S, Piloto O, Levis M, Li L, Chen P, Meltzer P, Small D. Constitutive Fms-like tyrosine kinase 3 activation results in specific changes in gene expression in myeloid leukaemic cells. Br J Haematol. 2007;138:603–15.PubMedCrossRef
61.
Faderl S, O’Brien S, Pui C-H, Stock W, Wetzler M, Hoelzer D, Kantarjian HM. Adult acute lymphoblastic leukemia: concepts and strategies. Cancer. 2010;116:1165–76.PubMedPubMedCentralCrossRef
62.
Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, Civin C, Scheibner K, Rassool F. c-MYC generates repair errors via increased transcription of alternative-NHEJ factors, LIG3 and PARP1, in tyrosine kinase-activated leukemias. Mol Cancer Res. 2015;13:699–712.PubMedPubMedCentralCrossRef
63.
Cavelier C, Didier C, Prade N, Mansat-De Mas V, Manenti S, Recher C, Demur C, Ducommun B. Constitutive activation of the DNA damage signaling pathway in acute myeloid leukemia with complex karyotype: potential importance for checkpoint targeting therapy. Cancer Res. 2009;69:8652–61.PubMedCrossRef
64.
Iacobucci I, Di Rorà AGL, Falzacappa MVV, Agostinelli C, Derenzini E, Ferrari A, Papayannidis C, Lonetti A, Righi S, Imbrogno E, Pomella S, Venturi C, Guadagnuolo V, Cattina F, Ottaviani E, Abbenante MC, Vitale A, Elia L, Russo D, Zinzani PL, Pileri S, Pelicci PG, Martinelli G. In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia. J Hematol Oncol. 2015;8:125.PubMedPubMedCentralCrossRef
65.
Sarmento LM, Póvoa V, Nascimento R, Real G, Antunes I, Martins LR, Moita C, Alves PM, Abecasis M, Moita LF, Parkhouse RME, Meijerink JPP, Barata JT. CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress. Oncogene. 2015;34(23):2978–90.PubMedCrossRef
66.
Nieborowska-Skorska M, Stoklosa T, Datta M, Czechowska A, Rink L, Slupianek A, Koptyra M, Seferynska I, Krszyna K, Blasiak J, Skorski T. ATR-Chk1 axis protects BCR/ABL leukemia cells from the lethal effect of DNA double-strand breaks. Cell Cycle. 2006;5:994–1000.PubMedCrossRef
67.
Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NMB, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GCM. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 2004;64:9152–9.PubMedCrossRef
68.
Korwek Z, Sewastianik T, Bielak-Zmijewska A, Mosieniak G, Alster O, Moreno-Villaneuva M, Burkle A, Sikora E. Inhibition of ATM blocks the etoposide-induced DNA damage response and apoptosis of resting human T cells. DNA Repair (Amst). 2012;11:864–73.CrossRef
69.
Batey MA, Zhao Y, Kyle S, Richardson C, Slade A, Martin NMB, Lau A, Newell DR, Curtin NJ. Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer. Mol Cancer Ther. 2013;12:959–67.PubMedPubMedCentralCrossRef
70.
Grosjean-Raillard J, Tailler M, Adès L, Perfettini J-L, Fabre C, Braun T, De Botton S, Fenaux P, Kroemer G. ATM mediates constitutive NF-kappaB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia. Oncogene. 2009;28:1099–109.PubMedCrossRef
71.
Nishida H, Tatewaki N, Nakajima Y, Magara T, Ko KM, Hamamori Y, Konishi T. Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Res. 2009;37:5678–89.PubMedPubMedCentralCrossRef
72.
Charrier JD, Durrant SJ, Golec JMC, Kay DP, Knegtel RMA, MacCormick S, Mortimore M, O’Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PSH, Young SC, Pollard JR. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011;54:2320–30.PubMedCrossRef
73.
Šalovská B, Fabrik I, Ďurišová K, Link M, Vávrová J, Řezáčová M, Tichý A. Radiosensitization of human leukemic HL-60 cells by ATR kinase inhibitor (VE-821): phosphoproteomic analysis. Int J Mol Sci. 2014;15:12007–26.PubMedPubMedCentralCrossRef
74.
Fokas E, Prevo R, Hammond EM, Brunner TB, McKenna WG, Muschel RJ. Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treat Rev. 2014;109–117.
75.
Pires IM, Olcina MM, Anbalagan S, Pollard JR, Reaper PM, Charlton PA, McKenna WG, Hammond EM. Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. Br J Cancer. 2012;107:291–9.PubMedPubMedCentralCrossRef
76.
Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG, Muschel RJ, Brunner TB. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012;13:1072–81.PubMedPubMedCentralCrossRef
77.
Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W, Muschel RJ, Brunner TB. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3, e441.PubMedPubMedCentralCrossRef
78.
Vávrová J, Zárybnická L, Lukášová E, Řezáčová M, Novotná E, Sinkorová Z, Tichý A, Pejchal J, Durišová K. Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60). Radiat Environ Biophys. 2013;52:471–9.PubMedCrossRef
79.
Jossé R, Martin SE, Guha R, Ormanoglu P, Pfister TD, Reaper PM, Barnes CS, Jones J, Charlton P, Pollard JR, Morris J, Doroshow JH, Pommier Y. ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014;74:6968–78.PubMedPubMedCentralCrossRef
80.
Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y, Hare B, Johnson MA, Milton S, Murphy CE, Takemoto D, Tolman C, Wood M, Charlton P, Charrier J-D, Furey B, Golec J, Reaper PM, Pollard JR. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970. Oncotarget. 2014;5:5674–85.PubMedPubMedCentralCrossRef
81.
Jones CD, Blades K, Foote KM, Guichard SM, Jewsbury, Philip J. McGuire T, Nissink JW, Odedra R, Tam K, Thommes P, Turner P, Wilkinson G, Wood C, Yates JW. Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; 2013.
82.
Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ, Bakkenist CJ. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget. 2015;6:44289–305.PubMedPubMedCentral
83.
Menezes DL, Holt J, Tang Y, Feng J, Barsanti P, Pan Y, Ghoddusi M, Zhang W, Thomas G, Holash J, Lees E, Taricani L. A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol Cancer Res. 2014;13:0240.2014.
84.
Kwok M, Davies N, Agathanggelou A, Smith E, Petermann E, Yates E, Brown J, Lau A, Stankovic T. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway. Lancet. 2015;385 Suppl 1:S58.
85.
Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 2012;12:801–17.PubMedCrossRef
86.
Daud AI, Ashworth MT, Strosberg J, Goldman JW, Mendelson D, Springett G, Venook AP, Loechner S, Rosen LS, Shanahan F, Parry D, Shumway S, Grabowsky JA, Freshwater T, Sorge C, Kang SP, Isaacs R, Munster PN. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol. 2015;33:1060–6.PubMedCrossRef
87.
88.
Welch S, Hirte HW, Carey MS, Hotte SJ, Tsao MS, Brown S, Pond GR, Dancey JE, Oza AM. UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. Gynecol Oncol. 2007;106:305–10.PubMedCrossRef
89.
Ma CX, Ellis MJC, Petroni GR, Guo Z, Cai SR, Ryan CE, Craig Lockhart A, Naughton MJ, Pluard TJ, Brenin CM, Picus J, Creekmore AN, Mwandoro T, Yarde ER, Reed J, Ebbert M, Bernard PS, Watson M, Doyle LA, Dancey J, Piwnica-Worms H, Fracasso PM. A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat. 2013;137:483–92.PubMedCrossRef
90.
Engelke CG, Parsels LA, Qian Y, Zhang Q, Karnak D, Robertson JR, Tanska DM, Wei D, Davis MA, Parsels JD, Zhao L, Greenson JK, Lawrence TS, Maybaum J, Morgan MA. Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. Clin Cancer Res. 2013;19:4412–21.PubMedPubMedCentralCrossRef
91.
Grabauskiene S, Bergeron EJ, Chen G, Chang AC, Lin J, Thomas DG, Giordano TJ, Beer DG, Morgan MA, Reddy RM. CHK1 levels correlate with sensitization to pemetrexed by CHK1 inhibitors in non-small cell lung cancer cells. Lung Cancer. 2013;82:477–84.PubMedPubMedCentralCrossRef
92.
Dai Y, Chen S, Kmieciak M, Zhou L, Lin H, Pei X-Y, Grant S. The novel Chk1 inhibitor MK-8776 sensitizes human leukemia cells to HDAC inhibitors by targeting the intra-S checkpoint and DNA replication and repair. Mol Cancer Ther. 2013;12:878–89.PubMedPubMedCentralCrossRef
93.
Zemanova J, Hylse O, Collakova J, Vesely P, Oltova A, Borsky M, Zaprazna K, Kasparkova M, Janovska P, Verner J, Kohoutek J, Dzimkova M, Bryja V, Jaskova Z, Brychtova Y, Paruch K, Trbusek M. Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells. Oncotarget. 2016;7.
94.
Morgan MA, Parsels LA, Zhao L, Parsels JD, Davis MA, Hassan MC, Arumugarajah S, Hylander-Gans L, Morosini D, Simeone DM, Canman CE, Normolle DP, Zabludoff SD, Maybaum J, Lawrence TS. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res. 2010;70:4972–81.PubMedPubMedCentralCrossRef
95.
Landau HJ, McNeely SC, Nair JS, Comenzo RL, Asai T, Friedman H, Jhanwar SC, Nimer SD, Schwartz GK. The checkpoint kinase inhibitor AZD7762 potentiates chemotherapy-induced apoptosis of p53-mutated multiple myeloma cells. Mol Cancer Ther. 2012;1781–1788.
96.
Didier C, Demur C, Grimal F, Jullien D, Manenti S, Ducommun B. Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype. Cancer Biol Ther. 2012;13:307–13.PubMedPubMedCentralCrossRef
97.
Kim MK, James J, Annunziata CM. Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells. BMC Cancer. 2015;15:1–10.CrossRef
98.
Nguyen T, Hawkins E, Kolluri A, Kmieciak M, Park H, Lin H, Grant S. Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL+ leukemia cells. Leuk Res. 2015;39:65–71.PubMedCrossRef
99.
Calvo E, Chen VJ, Marshall M, Ohnmacht U, Hynes SM, Kumm E, Diaz HB, Barnard D, Merzoug FF, Huber L, Kays L, Iversen P, Calles A, Voss B, Lin AB, Dickgreber N, Wehler T, Sebastian M. Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer. Investig New Drugs. 2014;955–968.
100.
King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W, Cox K, Guo S, Marshall M. Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2014;32:213–26.PubMedCrossRef
101.
Zhao J, Niu X, Li X, Edwards H, Wang G, Wang Y, Taub JW, Lin H, Ge Y. Inhibition of CHK1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Oncotarget. 2016;7:16–8.
102.
King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS. LY2606368 causes replication catastrophe and anti-tumor effects through CHK1-dependent mechanisms. Mol Cancer Ther. 2015.
103.
Di Rorà AGL, Iacobucci I, Imbrogno E, Papayannidis C, Derenzini E, Ferrari A, Guadagnuolo V, Robustelli V, Parisi S, Sartor C, Abbenante MC, Paolini S, Martinelli G. Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T-cell progenitor acute lymphoblastic leukemia. Oncotarget. 2016;7:53377–91.PubMedCentral
104.
Panek RL, Lu GH, Klutchko SR, Batley BL, Dahring TK, Hamby JM, Hallak H, Doherty AM, Keiser JA. In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. J Pharmacol Exp Ther. 1997;283:1433–44.PubMed
105.
Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, Sun Y. Radiosensitization of p53 mutant cells by PD0166285, a novel G2 checkpoint abrogator. Cancer Res. 2001;61:8211–7.PubMed
106.
Hirai H, Iwasawa Y, Okada M, Arai T, Nishibata T, Kobayashi M, Kimura T, Kaneko N, Ohtani J, Yamanaka K, Itadani H, Takahashi-Suzuki I, Fukasawa K, Oki H, Nambu T, Jiang J, Sakai T, Arakawa H, Sakamoto T, Sagara T, Yoshizumi T, Mizuarai S, Kotani H. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Cancer Ther. 2009;8:2992–3000.PubMedCrossRef
107.
Hirai H, Arai T, Okada M, Nishibata T, Kobayashi M, Sakai N, Imagaki K, Ohtani J, Sakai T, Yoshizumi T, Mizuarai S, Iwasawa Y, Kotani H. MK-1775, a small molecule Wee1 inhibitor, enhances antitumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010;9:514–22.PubMedCrossRef
108.
Bridges KA, Hirai H, Buser CA, Brooks C, Liu H, Buchholz TA, Molkentine JM, Mason KA, Meyn RE. MK-1775, a novel wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011;17:5638–48.PubMedPubMedCentralCrossRef
109.
Kreahling JM, Gemmer JY, Reed D, Letson D, Bui M, Altiok S. MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Mol Cancer Ther. 2012;11:174–82.PubMedCrossRef
110.
Van Linden AA, Baturin D, Ford JB, Fosmire SP, Gardner L, Korch C, Reigan P, Porter CC. Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol Cancer Ther. 2013;12:2675–84.PubMedPubMedCentralCrossRef
111.
Qi W, Xie C, Li C, Caldwell J, Edwards H, Taub JW, Wang Y, Lin H, Ge Y. CHK1 plays a critical role in the anti-leukemic activity of the wee1 inhibitor MK-1775 in acute myeloid leukemia cells. J Hematol Oncol. 2014;7:53.PubMedPubMedCentralCrossRef
112.
Zhou L, Zhang Y, Chen S, Kmieciak M, Leng Y, Lin H, Rizzo KA, Dumur CI, Ferreira-Gonzalez A, Dai Y, Grant S. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. Leukemia. 2015;29:807–18.PubMedCrossRef
113.
Qi W, Zhang W, Edwards H, Chu R, Madlambayan GJ, Taub JW, Wang Z, Wang Y, Li C, Lin H, Ge Y. Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. Cancer Biol Ther. 2015.
114.
Chaudhuri L, Vincelette ND, Koh BD, Naylor RM, Flatten KS, Peterson KL, McNally A, Gojo I, Karp JE, Mesa RA, Sproat LO, Bogenberger JM, Kaufmann SH, Tibes R. CHK1 and WEE1 inhibition combine synergistically to enhance therapeutic efficacy in acute myeloid leukemia ex vivo. Haematologica. 2014;99:688–96.PubMedPubMedCentralCrossRef
115.
Guertin AD, Martin MM, Roberts B, Hurd M, Qu X, Miselis NR, Liu Y, Li J, Feldman I, Benita Y, Bloecher A, Toniatti C, Shumway SD. Unique functions of CHK1 and WEE1 underlie synergistic anti-tumor activity upon pharmacologic inhibition. Cancer Cell Int. 2012;12:45.PubMedPubMedCentralCrossRef
116.
Russell MR, Levin K, Rader J, Belcastro L, Li Y, Martinez D, Pawel B, Shumway SD, Maris JM, Cole KA. Combination therapy targeting the Chk1 and Wee1 kinases shows therapeutic efficacy in neuroblastoma. Cancer Res. 2013;73:776–84.PubMedCrossRef
117.
Tibes R, Bogenberger JM, Chaudhuri L, Hagelstrom RT, Chow D, Buechel ME, Gonzales IM, Demuth T, Slack J, Mesa RA, Braggio E, Yin HH, Arora S, Azorsa DO. RNAi screening of the kinome with cytarabine in leukemias. Blood. 2012;119:2863–72.PubMedCrossRef
118.
Ford JB, Baturin D, Burleson TM, Van Linden AA, Kim Y, Porter CC. AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair. Oncotarget. 2015;6:28001–10.PubMedPubMedCentralCrossRef
119.
Scagliotti G, Kang JH, Smith D, Rosenberg R, Park K, Kim SW, Su WC, Boyd TE, Richards DA, Novello S, Hynes SM, Myrand SP, Lin J, Smyth EN, Wijayawardana S, Lin AB, Pinder-Schenck M. Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer. Invest New Drugs. 2016;34:625–35.PubMedCrossRef
120.
Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, Kummar S. Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol. 2015;33:3409–15.PubMedPubMedCentralCrossRef
121.
Lopez de Mesa R, Lopez de Cerain Salsamendi A, Ariznabarreta LS, Calasanz Abinzano MJ, Patino-Garcia A. Measurement and analysis of the chemotherapy-induced genetic instability in pediatric cancer patients. Mutagenesis. 2002;17:171–5.PubMedCrossRef
122.
Kamat N, Khidhir MA, Hussain S, Alashari MM, Rannug U. Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients. Cancer Cell Int. 2014;1–9.
123.
Finette BA, Homans AC, Albertini RJ. Emergence of genetic instability in children treated for leukemia. Science. 2000;288:514–7.PubMedCrossRef
Metadata
Title
The cell cycle checkpoint inhibitors in the treatment of leukemias
Authors
A. Ghelli Luserna di Rora’
I. Iacobucci
G. Martinelli
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0443-x

Other articles of this Issue 1/2017

Journal of Hematology & Oncology 1/2017 Go to the issue

Letter to the Editor

A novel monoclonal antibody against the von Willebrand Factor A2 domain reduces its cleavage by ADAMTS13

Review

The use of immunotherapy in the treatment of melanoma

Research

RETRACTED ARTICLE: MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway

Review

Wnt/beta-catenin pathway: modulating anticancer immune response

Research

Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein

Erratum

Erratum to: Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits