Cytotoxicity and Differentiating Effect of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Myelodysplastic Syndromes

Abstract

Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid diseases, characterized by frequent genetic/chromosomal aberrations. Olaparib is a potent, orally bioavailable poly(ADP-ribose) polymerase 1 (PARP1) inhibitor with acceptable toxicity profile, designed as targeted therapy for DNA repair defective tumors. Here, we investigated olaparib activity in primary cultures of bone marrow mononuclear cells collected from patients with MDS (n = 28). A single treatment with olaparib induced cytotoxic effects in most samples, with median IC50 of 5.4 µM (2.0–24.8 µM), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of γH2AX positive cells in samples with low IC50s. Olaparib preferentially killed myeloid cells causing a significant reduction of blasts and promyelocytes, paralleled by an increase in metamyelocytes and mature granulocytes while sparing lymphocytes that are not part of the MDS clone. Consistently, flow cytometry analysis revealed a decrease of CD117+/CD123+ immature progenitors (p < 0.001) and induction of CD11b+/CD16+ (p < 0.001) and CD10+/CD15+ (p < 0.01) neutrophils. Morphological and immunophenotypic changes were associated with a dose-dependent increase of PU.1 and CEBPA transcription factors, which are drivers of granulocytic and monocytic differentiation. Moreover, the combination of olaparib with decitabine resulted in augmented cytotoxic and differentiating effects. Our data suggest that olaparib may have therapeutic potential in MDS patients.

Olaparib dose re‐escalation in ovarian cancer patients who experienced severe and/or uncommon adverse events: A case series

“…Chemotherapy also carries a several‐fold increased risk of tMN, especially in younger patients 29 . There were concerns over a 0.8–2% risk of tMN in previous olaparib OC trials 29 and, in vitro , olaparib induced apoptosis of myeloid cells 30 . An increased risk of tMN versus placebo was not reproduced in SOLO2 and other recent PARP inhibitor trials, suggesting that the previous incidences might have been attributable to prior cytotoxic treatment(s) 30 .…”

“…There were concerns over a 0.8–2% risk of tMN in previous olaparib OC trials 29 and, in vitro , olaparib induced apoptosis of myeloid cells 30 . An increased risk of tMN versus placebo was not reproduced in SOLO2 and other recent PARP inhibitor trials, suggesting that the previous incidences might have been attributable to prior cytotoxic treatment(s) 30 . In terms of BRCA mutation status, whereas an in vitro study suggested that impaired DNA homologous recombination repair mechanisms in BRCA ‐mutated cell lines may increase the efficacy of olaparib + chemotherapy combination treatment 31 ; the effect on toxicity has yet to be studied.…”

The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors

“…Therefore, PARP inhibitors can also be considered as guardians of stem cell reservoirs. In the culture of primary bone marrow mononuclear cells collected from patients with myelodysplastic syndromes, olaparib revealed toxicity against myeloid cells, causing a significant reduction of blasts and promyelocytes, but increased the number of metamyelocytes and mature granulocytes by promoting a dose-dependent increase of PU.1 and CEBPA transcription factors, which drive the differentiation of granulocytes and monocytes [ 137 ]. In line with these findings is another set of data from the culture of BCR‒ABL1 -positive HSC, which lost repopulation activity upon PARP inhibition [ 138 ].…”

PARP Inhibitors and Haematological Malignancies—Friend or Foe?

“…Combining veliparib and busulfan enhances cell death in primary MF patient samples ex vivo, and in a JAK2V617F MPN-AML xenotransplant model in vivo [ 93 ], thus demonstrating that inherent resistance to PARPi does not prevent PARPi from sensitising these cells to other anti-cancer drugs. Additionally, combining olaparib and decitabine or olaparib/talazoparib and ruxolitinib and/or hydroxyurea increases cell death compared to either agent alone [ 94 , 95 ].…”