Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair

Ida,Naoko; Okura,Miyuki; Tanaka,Saki; Hosono,Naoko; Yamauchi,Takahiro

doi:10.3892/or.2024.8749

Combining inotuzumab ozogamicin with PARP inhibitors olaparib and talazoparib exerts synergistic cytotoxicity in acute lymphoblastic leukemia by inhibiting DNA strand break repair

Authors:
- Naoko Ida
- Miyuki Okura
- Saki Tanaka
- Naoko Hosono
- Takahiro Yamauchi
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Affiliations: Department of Hematology and Oncology, University of Fukui, Matsuoka, Eiheiji, Fukui 910‑1193, Japan, Department of Blood Transfusion, University of Fukui Hospital, Matsuoka, Eiheiji, Fukui 910‑1193, Japan
Published online on: May 21, 2024 https://doi.org/10.3892/or.2024.8749
Article Number: 90

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Abstract

Inotuzumab ozogamicin (IO), a novel therapeutic drug for relapsed or refractory acute lymphoblastic leukemia (RR)‑(ALL), is a humanized anti‑cluster of differentiation (CD) 22 monoclonal antibody conjugated with calicheamicin that causes DNA single‑ and double‑strand breaks. Although the efficacy of IO is significantly improved compared with that of conventional chemotherapies, the prognosis for RR‑ALL remains poor, highlighting the need for more effective treatment strategies. The present study examined the role of DNA damage repair inhibition using the poly (ADP‑ribose) polymerase (PARP) inhibitors olaparib or talazoparib on the enhancement of the antitumor effects of IO on B‑ALL cells in vitro. The Reh, Philadelphia (Ph)^‑B‑ALL and the SUP‑B15 Ph⁺ B‑ALL cell lines were used for experiments. Both cell lines were ~90% CD22⁺. The half‑maximal inhibitory concentration (IC₅₀) values of IO were 5.3 and 49.7 ng/ml for Reh and SUP‑B15 cells, respectively. The IC₅₀ values of IO combined with minimally toxic concentrations of olaparib or talazoparib were 0.8 and 2.9 ng/ml for Reh cells, respectively, and 36.1 and 39.6 ng/ml for SUP‑B15 cells, respectively. The combination index of IO with olaparib and talazoparib were 0.19 and 0.56 for Reh cells and 0.76 and 0.89 for SUP‑B15 cells, demonstrating synergistic effects in all combinations. Moreover, the addition of minimally toxic concentrations of PARP inhibitors augmented IO‑induced apoptosis. The alkaline comet assay, which quantitates the amount of DNA strand breaks, was used to investigate the degree to which DNA damage observed 1 h after IO administration was repaired 6 h later, reflecting successful repair of DNA strand breaks. However, DNA strand breaks persisted 6 h after IO administration combined with olaparib or talazoparib, suggesting inhibition of the repair processes by PARP inhibitors. Adding olaparib or talazoparib thus synergized the antitumor effects of IO by inhibiting DNA strand break repair via the inhibition of PARP.

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1	Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, Ferrara F, Peta A, Ciolli S, Deplano W, et al: Treatment of adult acute lymphoblastic leukemia (ALL): Long-Term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 99:863–871. 2002. View Article : Google Scholar : PubMed/NCBI
2	Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, Kuriyama K, Ohtake S, Yagasaki F, Murakami H, et al: Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: The JALSG-ALL93 study. Leukemia. 16:1259–1266. 2002. View Article : Google Scholar : PubMed/NCBI
3	Gökbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Hüttmann A, Kobbe G, Kreuzer KA, Leimer L, Reichle A, et al: Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 120:2032–2041. 2012. View Article : Google Scholar : PubMed/NCBI
4	Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O'Brien S, Wang K, Wang T, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 375:740–753. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, O'Brien SM, Jabbour E, Wang T, Liang White J, et al: Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 125:2474–2487. 2019. View Article : Google Scholar : PubMed/NCBI
6	Kantarjian HM, Su Y, Jabbour EJ, Bhattacharyya H, Yan E, Cappelleri JC and Marks DI: Patient-Reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Cancer. 124:2151–2160. 2018. View Article : Google Scholar : PubMed/NCBI
7	de Vries JF, Zwaan CM, De Bie M, Voerman JSA, den Boer ML, van Dongen JJM and van der Velden VHJ: The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia. 26:255–264. 2012. View Article : Google Scholar : PubMed/NCBI
8	Rose M, Burgess JT, O'Byrne K, Richard DJ and Bolderson E: PARP inhibitors: Clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol. 8:5646012020. View Article : Google Scholar : PubMed/NCBI
9	DiSilvestro P, Colombo N, Harter P, González-Martín A, Ray-Coquard I and Coleman RL: Maintenance treatment of newly diagnosed advanced ovarian cancer: Time for a paradigm shift? Cancers (Basel). 13:57562021. View Article : Google Scholar : PubMed/NCBI
10	Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ and Helleday T: Specific killing of BRCA2-Deficient tumours with inhibitors of poly(ADP-Ribose) polymerase. Nature. 434:913–917. 2005. View Article : Google Scholar : PubMed/NCBI
11	Cortesi L, Rugo HS and Jackisch C: An overview of PARP inhibitors for the treatment of breast cancer. Targ Oncol. 16:255–282. 2021. View Article : Google Scholar : PubMed/NCBI
12	Chou TC: Drug combination studies and their synergy quantification using the chou-talalay method. Cancer Res. 70:440–446. 2010. View Article : Google Scholar : PubMed/NCBI
13	Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P and Carroll WL: Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-Lymphoblastic leukemia. Blood. 119:5201–5210. 2012. View Article : Google Scholar : PubMed/NCBI
14	Uy N, Nadeau M, Stahl M and Zeidan AM: Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia. J Blood Med. 9:67–74. 2018. View Article : Google Scholar : PubMed/NCBI
15	Pardee TS, Stadelman K, Gee JJ, Caudell DL and Gmeiner WH: The poison oligonucleotide F10 is highly effective against acute lymphoblastic leukemia while sparing normal hematopoietic cells. Oncotarget. 5:4170–4179. 2014. View Article : Google Scholar : PubMed/NCBI
16	Punzo F, Argenziano M, Tortora C, Paola AD, Mutarelli M, Pota E, Martino MD, Pinto DD, Marrapodi MM, Roberti D, et al: Effect of CB2 stimulation on gene expression in pediatric B-Acute lymphoblastic leukemia: New possible targets. Int J Mol Sci. 23:86512022. View Article : Google Scholar : PubMed/NCBI
17	Kumaravel TS, Vilhar B, Faux SP and Jha AN: Comet assay measurements: A perspective. Cell Biol Toxicol. 25:53–64. 2009. View Article : Google Scholar : PubMed/NCBI
18	Madhusudan S and Hickson ID: DNA Repair inhibition: A selective tumour targeting strategy. Trends Mol Med. 11:503–511. 2005. View Article : Google Scholar : PubMed/NCBI
19	Moynahan ME and Jasin M: Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 11:196–207. 2010. View Article : Google Scholar : PubMed/NCBI
20	Ceccaldi R, Rondinelli B and D'Andrea AD: Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 26:52–64. 2016. View Article : Google Scholar : PubMed/NCBI
21	O'Connor MJ: Targeting the DNA damage response in cancer. Mol Cell. 60:547–560. 2015. View Article : Google Scholar : PubMed/NCBI
22	Elmroth K, Nygren J, Mårtensson S, Ismail IH and Hammarsten O: Cleavage of cellular DNA by calicheamicin gamma1. DNA Repair (Amst). 2:363–374. 2003. View Article : Google Scholar : PubMed/NCBI
23	Javle M and Curtin NJ: The role of PARP in DNA repair and its therapeutic exploitation. Br J Cancer. 105:1114–1122. 2011. View Article : Google Scholar : PubMed/NCBI
24	Mariano G, Ricciardi MR, Trisciuoglio D, Zampieri M, Ciccarone F, Guastafierro T, Calabrese R, Valentini E, Tafuri A, Bufalo DD, et al: PARP inhibitor ABT-888 affects response of MDA-MB-231 cells to doxorubicin treatment, targeting snail expression. Oncotarget. 6:15008–15021. 2015. View Article : Google Scholar : PubMed/NCBI
25	Wu J, Xiao S, Yuan M, Li Q, Xiao G, Wu W, Ouyang Y, Huang L and Yao C: PARP inhibitor re-sensitizes adriamycin resistant leukemia cells through DNA damage and apoptosis. Mol Med Rep. 19:75–84. 2019.PubMed/NCBI
26	Yamauchi T, Uzui K, Nishi R, Shigemi H and Ueda T: Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells. Anticancer Res. 34:5487–5494. 2014.PubMed/NCBI
27	Ariumi Y, Masutani M, Copeland TD, Mimori T, Sugimura T, Shimotohno K, Ueda K, Hatanaka M and Noda M: Suppression of the poly(ADP-Ribose) polymerase activity by DNA-dependent protein kinase in vitro. Oncogene. 18:4616–4625. 1999. View Article : Google Scholar : PubMed/NCBI
28	Galande S and Kohwi-Shigematsu T: Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically bind to matrix attachment sequences. J Biol Chem. 274:20521–20528. 1999. View Article : Google Scholar : PubMed/NCBI
29	Haince JF, Kozlov S, Dawson VL, Dawson TM, Hendzel MJ, Lavin MF and Poirier GG: Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem. 282:16441–16453. 2007. View Article : Google Scholar : PubMed/NCBI
30	Haince JF, McDonald D, Rodrigue A, Déry U, Masson JY, Hendzel MJ and Poirier GG: PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem. 283:1197–1208. 2008. View Article : Google Scholar : PubMed/NCBI
31	Tirrò E, Massimino M, Romano C, Pennisi MS, Stella S, Vitale SR, Fidilio A, Manzella L, Parrinello NL, Stagno F, et al: Chk1 inhibition restores inotuzumab ozogamicin citotoxicity in CD22-positive cells expressing mutant P53. Front Oncol. 9:572019. View Article : Google Scholar : PubMed/NCBI
32	Takeshita A, Shinjo K, Yamakage N, Ono T, Hirano I, Matsui H, Shigeno K, Nakamura S, Tobita T, Maekawa M, et al: CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: Analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma. Br J Haematol. 146:34–43. 2009. View Article : Google Scholar : PubMed/NCBI
33	Jabbour EJ, Sasaki K, Ravandi F, Short NJ, Garcia-Manero G, Daver N, Kadia T, Konopleva M, Jain N, Cortes J, et al: Inotuzumab ozogamicin in combination with low-intensity chemotherapy (Mini-HCVD) with or without blinatumomab versus standard intensive chemotherapy (HCVAD) as frontline therapy for older patients with philadelphia chromosome-negative acute lymphoblastic leukemia: A propensity score analysis. Cancer. 125:2579–2586. 2019. View Article : Google Scholar : PubMed/NCBI
34	Kantarjian H, Haddad FG, Jain N, Sasaki K, Short NJ, Loghavi S, Kanagal-Shamanna R, Jorgensen J, Khouri I, Kebriaei P, et al: Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia. J Hematol Oncol. 16:442023. View Article : Google Scholar : PubMed/NCBI
35	Javad N, Francisca V and James MM: Bridging the gap between cancer cell line models and tumours using gene expression data. Br J Cancer. 125:311–312. 2021. View Article : Google Scholar
36	Wilding JL and Bodmer WF: Cancer cell lines for drug discovery and development. Cancer Res. 74:2377–2384. 2014. View Article : Google Scholar : PubMed/NCBI
37	Ricart AD: Antibody-drug conjugates of calicheamicin derivative: Gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin Cancer Res. 17:6417–6427. 2011. View Article : Google Scholar : PubMed/NCBI
38	Yonemori K, Tamura K, Kodaira M, Fujikawa K, Sagawa T, Esaki T, Shirakawa T, Hirai F, Yokoi Y, Kawata T, et al: Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Cancer Chemother Pharmacol. 78:525–531. 2016. View Article : Google Scholar : PubMed/NCBI
39	Naito Y, Kuboki Y, Ikeda M, Harano K, Matsubara N, Toyoizumi S, Mori Y, Hori N, Nagasawa T and Kogawa T: Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: Phase 1 study. Invest New Drugs. 39:1568–1576. 2021. View Article : Google Scholar : PubMed/NCBI
40	Lee JM, Peer CJ, Yu M, Amable L, Gordon N, Annunziata CM, Houston N, Goey AKL, Sissung TM, Parker B, et al: Sequence-specific pharmacokinetic and pharmacodynamic phase I/Ib study of olaparib tablets and carboplatin in Women's cancer. Clin Cancer Res. 23:1397–1406. 2017. View Article : Google Scholar : PubMed/NCBI
41	Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, Shen L, Qin S, Xu N, Im SA, et al: Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 18:1637–1651. 2017. View Article : Google Scholar : PubMed/NCBI
42	Oza AM, Cibula D, Benzaquen AO, Poole C, Mathijissen RHJ, Sonke GS, Colombo N, Spacek J, Vuylsteke P, Hirte H, et al: Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: A randomised phase 2 trial. Lamcet Oncol. 16:87–97. 2015. View Article : Google Scholar
43	Lai Y, Wei X, Lin S, Qin L, Cheng L and Li P: Current status and perspectives of patient-derived xenograft models in cancer research. J Hematol Oncol. 10:1062017. View Article : Google Scholar : PubMed/NCBI