PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.

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Micro-irradiation tools to visualize base excision repair and single-strand break repair

DNA Repair ◽

10.1016/j.dnarep.2015.05.001 ◽

2015 ◽

Vol 31 ◽

pp. 52-63 ◽

Cited By ~ 29

Author(s):

Natalie R. Gassman ◽

Samuel H. Wilson

Keyword(s):

Base Excision Repair ◽

Excision Repair ◽

Strand Break ◽

Single Strand ◽

Single Strand Break ◽

Single Strand Break Repair ◽

Break Repair ◽

Base Excision

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Quantitation of intracellular NAD(P)H can monitor an imbalance of DNA single strand break repair in base excision repair deficient cells in real time

Nucleic Acids Research ◽

10.1093/nar/gng105 ◽

2003 ◽

Vol 31 (17) ◽

pp. 104e-104 ◽

Cited By ~ 41

Author(s):

J. Nakamura

Keyword(s):

Real Time ◽

Base Excision Repair ◽

Excision Repair ◽

Strand Break ◽

Single Strand ◽

Single Strand Break ◽

Single Strand Break Repair ◽

Break Repair ◽

Base Excision

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Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in tumors for personalized cancer therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1014 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1014-1014

Author(s):

Srinivasan Madhusudan ◽

Tarek M. A. Abdel-Fatah ◽

Rebeka Sultana ◽

Rachel Abbotts ◽

Claire Hawkes ◽

...

Keyword(s):

Synthetic Lethality ◽

Excision Repair ◽

Human Cancer ◽

Chinese Hamster ◽

Fold Increase ◽

Strand Break ◽

Poor Survival ◽

Single Strand Break ◽

Risk Of Death ◽

Break Repair

1014 Background: XRCC1 is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. XRCC1 deficiency promotes genomic instability and may increase cancer risk. Methods: We evaluated XRCC1 immunohistochemically in early stage breast (n=2046), ovarian (n=157), gastric (n=140), colorectal (n=250) and pancreaticobiliary cancers (n=240). Pre-clinically, we evaluated a panel of XRCC1 deficient and proficient Chinese hamster ovary and human cancer cell lines. Double strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs (NU7441) and ATR (NU6027) were evaluated for synthetic lethality and cisplatin alone or in combination with DSB inhibitors for chemopotentiation. Results: In breast cancer,XRCC1 loss (16%) was associated with higher grade (p<0.0001), loss of hormone receptors (p<0.0001), presence of triple negative (p<0.0001) and basal like phenotypes (p=0.001). Loss of XRCC1 was associated with a 2-fold increase in risk of death and metastasis (p<0.0001) and independently with poor outcome (p<0.0001). In ovarian cancer, XRCC1 was positive in 44% of tumour and was significantly associated with higher stage (p=0.001), clear/endometroid type (p=0.015) and sub-optimal debulking (p=0.004). XRCC1 positive tumours were more resistant to platinum chemotherapy (p=0.0001). XRCC1 positivity conferred a 2 fold increase of risk of death (p=0.002) and independently associated with poor survival (p=0.002). In gastric cancers, XRCC1 was positive in 37% of tumours. This was significantly associated with high stage disease (p=0.001) and poor survival (p=0.001). Pre-clinically, KU55933, NU7441 and NU6027 were synthetically lethal in XRCC1 deficient compared to proficient cells as evidenced by DSB accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells were hypersensitive to cisplatin which was enhanced by DSB repair inhibitors compared to in proficient cells. Conclusions: This is the largest study to confirm the clinical significance of XRCC1 expression in solid tumours. XRCC1 deficiency in human tumours may be suitable for synthetic lethality application and exploited for cisplatin chemotherapy potentiation.

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Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22115475 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5475

Author(s):

Griffin Wright ◽

Manoj Sonavane ◽

Natalie R. Gassman

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Excision Repair ◽

Strand Break ◽

Xrcc1 Gene ◽

Single Strand Break ◽

Expression Levels ◽

Constitutive Activation ◽

Gene And Protein Expression

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.

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