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

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

  • J Transl Med. 2024 Nov 26;22(1):1062. doi: 10.1186/s12967-024-05838-9.
Andrea Ghelli Luserna di Rorà 1 2,  Mouna Jandoubi # 1,  Antonella Padella # 1 3,  Anna Ferrari 4,  Andrea Marranci 2,  Cristina Mazzotti 1,  Francesco Olimpico 2,  Martina Ghetti 1,  Lorenzo Ledda 1,  Maria Teresa Bochicchio 1,  Matteo Paganelli 1,  Michele Zanoni 1,  Alessandro Cafaro 5,  Chiara Servili 1,  Sara Galimberti 6,  Michele Gottardi 7,  Michela Rondoni 8,  Mauro Endri 9,  Daniela Onofrillo 10,  Ernesta Audisio 11,  Giovanni Marconi 1,  Giorgia Simonetti 1,  Giovanni Martinelli 12
Affiliations

Affiliations

  • 1 Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, 47014, Meldola, FC, Italy.
  • 2 Fondazione Pisana per la Scienza ONLUS, San Giuliano Terme, Italy.
  • 3 Wellmicro SPA, Bologna, Italy.
  • 4 Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, 47014, Meldola, FC, Italy. anna.ferrari@irst.emr.it.
  • 5 Pharmacy, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, 47014, Meldola, FC, Italy.
  • 6 Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, 56126, Pisa, Italy.
  • 7 Onco Hematology, Department of Oncology, Veneto Institute of Oncology, Istituto Oncologico Veneto-Istituto di Ricerca e Cura a Carattere Scientifico (IOV-IRCCS), Castelfranco Veneto, Italy.
  • 8 Hematology Unit & Romagna Transplant Network, Ravenna Hospital, Ravenna, Italy.
  • 9 Azienda ULSS 2 Marca Trevigiana Ospedale Ca' Foncello, Treviso, Italy.
  • 10 UOC di Ematologia, Dipartimento di Oncologia Ematologia, Ospedale Santo Spirito, Pescara, Italy.
  • 11 Hematology Unit, Presidio Ospedaliero Molinette, A.O.U. Città della Salute e Della Scienza, Turin, Italy.
  • 12 IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via Piero Maroncelli, 40, 47014, Meldola, FC, Italy.
  • # Contributed equally.
PMID: 39587643 DOI: 10.1186/s12967-024-05838-9
Abstract

Background: The 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.

Methods: AML and ALL cells were treated with GO, INO and γ-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.

Results: We observed that both ALL and AML cell lines activate the G2/M cell-cycle checkpoint in response to γ-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.

Conclusion: PARP1 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 γ-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.

Keywords

Acute lymphoblastic leukemia (ALL); Acute myeloid leukemia (AML); Antibody–drug conjugates; DNA damage response pathway; PARP1 inhibition.

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