Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers

Janysek, Dawn; Kim, Jennifer; Duijf, Pascal H.G.; Dray, Eloïse

doi:10.1016/j.tranon.2021.101012

Cited by 33 publications

(25 citation statements)

References 147 publications

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“…The inhibition of this process is thought to be a canonical mechanism of action of PARP inhibitors. The second mechanism of action of PARP inhibitors is PARP trapping where activated PARP molecules are trapped onto damaged DNA, thereby blocking DNA repair proteins from DNA replication and leading to accumulation of singlestranded DNA breaks, induction of double strand breaks and cell death [18,19]. More recently, a third and possibly unifying mechanism has been proposed for PARP sensitivity that relates to replication gap formation, a phenotype that is rescued by loss of p53-binding protein 1 (53BP1) [20].…”

Section: Description Of Dna Repair Damage Process and Parp Synthetic Lethalitymentioning

confidence: 99%

PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Chan

Brown

Reid

et al. 2021

Cancers

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Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

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Section: Description Of Dna Repair Damage Process and Parp Synthetic Lethalitymentioning

confidence: 99%

PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Chan

Brown

Reid

et al. 2021

Cancers

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“…PARP1 inhibitor AZD2281 was more effective when coadministered with the P-glycoprotein inhibitor tariquidar [71][72][73]. Use of PARP inhibitors has been approved for treatment in BRCA1 and BRCA2 mutated breast and ovarian cancers, and for therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes [74]. Olaparib resistance may occur in cancers with homologous recombination defects [73].…”

Section: Parp1/2/3 Inhibitors In Cancer Treatmentmentioning

confidence: 99%

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Poltronieri¹,

Misawa²,

Masutani³

2021

Preprint

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Among post-translational modifications of proteins, ADP-ribosylation has been studied for over fifty years, assigning to this PTM a large set of functions, including DNA repair, transcription and cell signaling. This review presents an update on the function of a large set of enzyme writers, the readers that are recruited by the modified targets, and the erasers that reverse the modification to the original amino acid residue, removing the covalent bonds formed. In particular, the review provides details on the involvement of the enzymes performing MAR/PAR cycling in cancers. Of note, there is potential for application of the inhibitors developed for cancer also in the therapy of non-oncological diseases such as the protection against oxidative stress, suppression of inflammatory responses, and the treatment of neurodegenerative diseases. This field of studies is not concluded, since novel enzymes are being discovered at a rapid pace.

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“…A number of PARP inhibitors have been developed and may be used clinically to treat cancers with homologous recombination (HR) deficiency, such as those with mutations in BRCA1 , BRCA2 , and PALB2 . In these cancers, PARP inhibitors can induce synthetic lethality, and this approach has had some success particularly in breast and ovarian cancer ( Janysek et al, 2021 ). This synthetic lethality approach is unlikely to be widely successful in medulloblastoma, as very few patients harbor mutations in genes encoding HR machinery.…”

Section: Introductionmentioning

confidence: 99%

Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Buck

Dyer

Hii

et al. 2021

Front. Mol. Biosci.

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Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

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Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers

Cited by 33 publications

References 147 publications

PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

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