Exploring the role of PARP1 inhibition in enhancing antibody-drug conjugate therapy for acute leukemias: insights from DNA damage response pathway interactions

被引：0

作者：

Ghelli Luserna di Rora, Andrea ^{[1
,2
]}

Jandoubi, Mouna ^{[1
]}

Padella, Antonella ^{[1
,3
]}

Ferrari, Anna ^{[1
]}

Marranci, Andrea ^{[2
]}

Mazzotti, Cristina ^{[1
]}

Olimpico, Francesco ^{[2
]}

Ghetti, Martina ^{[1
]}

Ledda, Lorenzo ^{[1
]}

Bochicchio, Maria Teresa ^{[1
]}

Paganelli, Matteo ^{[1
]}

Zanoni, Michele ^{[1
]}

Cafaro, Alessandro ^{[4
]}

Servili, Chiara ^{[1
]}

Galimberti, Sara ^{[5
]}

Gottardi, Michele ^{[6
]}

Rondoni, Michela ^{[7
,8
]}

Endri, Mauro ^{[9
]}

Onofrillo, Daniela ^{[10
]}

Audisio, Ernesta ^{[11
]}

Marconi, Giovanni ^{[1
]}

Simonetti, Giorgia ^{[1
]}

Martinelli, Giovanni ^{[12
]}

机构：

[1] IRCCS Ist Romagnolo Studio Tumori IRST Dino Amador, Biosci Lab, Via Piero Maroncelli 40, I-47014 Meldola, FC, Italy

[2] Fdn Pisana Sci ONLUS, San Giuliano Terme, Italy

[3] Wellmicro SPA, Bologna, Italy

[4] IRCCS Ist Romagnolo Studio Tumori IRST Dino Amador, Pharm, Via Piero Maroncelli 40, I-47014 Meldola, FC, Italy

[5] Univ Pisa, Dept Clin & Expt Med, Sect Hematol, I-56126 Pisa, Italy

[6] Ist Ric & Cura Carattere Sci IOV IRCCS, Veneto Inst Oncol, Ist Oncol Veneto, Dept Oncol,Onco Hematol, Castelfranco Veneto, Italy

[7] Ravenna Hosp, Hematol Unit, Ravenna, Italy

[8] Ravenna Hosp, Romagna Transplant Network, Ravenna, Italy

[9] Azienda ULSS 2 Marca Trevigiana Osped Ca Foncello, Treviso, Italy

[10] Osped Santo Spirito, Dipartimento Oncol Ematol, UOC Ematol, Pescara, Italy

[11] AOU Citta Salute & Sci, Hematol Unit, Presidio Osped Molinette, Turin, Italy

[12] IRCCS Ist Romagnolo Studio Tumori IRST Dino Amador, Via Piero Maroncelli 40, I-47014 Meldola, FC, Italy

来源：

JOURNAL OF TRANSLATIONAL MEDICINE | 2024年 / 22卷 / 01期

关键词：

Antibody-drug conjugates; PARP1; inhibition; DNA damage response pathway; Acute myeloid leukemia (AML); Acute lymphoblastic leukemia (ALL); ACUTE MYELOID-LEUKEMIA; GEMTUZUMAB OZOGAMICIN; INOTUZUMAB OZOGAMICIN; CD33; EXPRESSION; CALICHEAMICIN; PHOSPHORYLATION; OLAPARIB; CMC-544; TARGET; REPAIR;

D O I：

10.1186/s12967-024-05838-9

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

BackgroundThe introduction of antibody-drug conjugates represents a significant advancement in targeted therapy of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Our study aims to investigate the role of the DNA damage response pathway and the impact of PARP1 inhibition, utilizing talazoparib, on the response of AML and ALL cells to Gemtuzumab ozogamicin (GO) and Inotuzumab ozogamicin (INO), respectively.MethodsAML and ALL cells were treated with GO, INO and gamma-calicheamicin in order to induce severe DNA damage and activate the G2/M cell-cycle checkpoint in a dose- and time-dependent manner. The efficacy of PARP1 inhibitors and, in particular, talazoparib in enhancing INO or GO against ALL or AML cells was assessed through measurements of cell viability, cell death, cell cycle progression, DNA damage repair, accumulation of mitotic DNA damage and inhibition of clonogenic capacity.ResultsWe observed that both ALL and AML cell lines activate the G2/M cell-cycle checkpoint in response to gamma-calicheamicin-induced DNA damage, highlighting a shared cellular response mechanism. Talazoparib significantly enhanced the efficacy of INO against ALL cell lines, resulting in reduced cell viability, increased cell death, G2/M cell-cycle checkpoint override, accumulation of mitotic DNA damage and inhibition of clonogenic capacity. Strong synergism was observed in primary ALL cells treated with the combination. In contrast, AML cells exhibited a heterogeneous response to talazoparib in combination with GO. Our findings suggest a potential link between the differential responses of ALL and AML cells to the drug combinations and the ability of talazoparibto override G2/M cell-cycle arrest induced by antibody-drug conjugates.ConclusionPARP1 emerges as a key player in the response of ALL cells to INO and represents a promising target for therapeutic intervention in this leukemia setting. Our study sheds light on the intricate interplay between the DNA damage response pathway, PARP1 inhibition, and response of gamma-calicheamicin-induced DNA damages in AML and ALL. These findings underscore the importance of targeted therapeutic strategies and pave the way for future research aimed at optimizing leukemia treatment approaches.

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页数：18