Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology

Mweempwa, Angela; Wilson, Michelle

doi:10.20517/cdr.2019.50

Cited by 8 publications

(11 citation statements)

References 71 publications

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“…The results were supported by immunostaining with specific antibodies (Figure 3B,D and Figure S1). Furthermore, decrease in BRCA1 was detected both in Wi-A and CAPE treated cells as compared to their untreated counterparts, and was consistent with earlier reports [62,63]. We next investigated if reduction in mortalin and PARP1 in Wi-A/CAPE-treated cells was interlinked.…”

Section: Wi-a and Cape Triggered Parp1 Cleavage And Apoptosis Signalingsupporting

confidence: 89%

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

Sari

Bhargava

Dhanjal

et al. 2020

Cancers

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We have earlier reported anticancer activity in Withaferin A (Wi-A), a withanolide derived from Ashwagandha (Withania somnifera) and caffeic acid phenethyl ester (CAPE), an active compound from New Zealand honeybee propolis. Whereas Wi-A was cytotoxic to both cancer and normal cells, CAPE has been shown to cause selective death of cancer cells. In the present study, we investigated the efficacy of Wi-A, CAPE, and their combination to ovarian and cervical cancer cells. Both Wi-A and CAPE were seen to activate tumor suppressor protein p53 by downregulation of mortalin and abrogation of its interactions with p53. Downregulation of mortalin translated to compromised mitochondria integrity and function that affected poly ADP-ribose polymerase1 (PARP1); a key regulator of DNA repair and protein-target for Olaparib, drugs clinically used for treatment of breast, ovarian and cervical cancers)-mediated DNA repair yielding growth arrest or apoptosis. Furthermore, we also compared the docking capability of Wi-A and CAPE to PARP1 and found that both of these could bind to the catalytic domain of PARP1, similar to Olaparib. We provide experimental evidences that (i) Wi-A and CAPE cause inactivation of PARP1-mediated DNA repair leading to accumulation of DNA damage and activation of apoptosis signaling by multiple ways, and (ii) a combination of Wi-A and CAPE offers selective toxicity and better potency to cancer cells.

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Section: Wi-a and Cape Triggered Parp1 Cleavage And Apoptosis Signalingsupporting

confidence: 89%

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

Sari

Bhargava

Dhanjal

et al. 2020

Cancers

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“…An improved understanding of the synthetic lethality strategies will probably extend the use of PARP inhibitors beyond tumors with BRCA1/2 mutations [68]. Aside from drug-drug interactions, known causes for OLA resistance include disturbed PARylation metabolism, alterations in drug transporters, up-regulation of HR, and replication forks [69][70][71].…”

Section: Discussionmentioning

confidence: 99%

“…Assuming that all the used inhibitors worked as in other models, one explanation regarding the resistance to BLEO + OLA + 3i would be that cells repaired DNA damage through a PARP-independent pathway rather than MMEJ (which is PARP-1 dependent) or HR (because ATM was inhibited) or c-NHEJ (since DNA-PK and LigIV were inhibited). Even under the HR defect (due to mutated or inhibited proteins), replication fork stabilization has been proposed as an alternative PARPis resistance mechanism [69,71]. According to Haynes et al [72], checkpoint kinases ATR, CHK1, and WEE1 play different roles in replication fork stabilization, providing alternative mechanisms to be considered in combination therapy development in order to avoid drug resistance.…”

Section: Discussionmentioning

confidence: 99%

PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

Perini

Schacke

Liddle

et al. 2020

IJMS

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Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.

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“…Although patients with HRR-related cancers have been shown to achieve high response rates to PARP inhibitor treatment, rates of pre-existing (intrinsic) and acquired resistance are high [45]. Several mechanisms of resistance for PARP inhibition have been proposed (Table 3), including restoration of HRR by a secondary (or reversion) mutation, changes in PARP1 (the primary target of PARP inhibitors), suppression of nonhomologous end joining, and replication fork protection [45][46][47][48]. Gaining a greater understanding of these mechanisms may help in selecting appropriate combination therapies to reduce resistance.…”

Section: Parp Inhibitor Resistancementioning

confidence: 99%

When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On-Going Trials

Antonarakis

Gomella

Petrylak

2020

European Urology Oncology

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Context: The goal of precision oncology is to use the underlying genomic characteristics of the patient and the cancer to select the optimal treatment at a given time. The recent Food and Drug Administration (FDA) approval of the poly(ADPribose) polymerase (PARP) inhibitors olaparib and rucaparib for the treatment of advanced prostate cancer heralds the onset of precision medicine for this disease. Objective: To discuss the emerging role that PARP inhibitors may play as a personalised future treatment option in patients with prostate cancer, with a focus on patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumour cells harbour mutations resulting from deficient homologous recombination repair (HRR). Evidence acquisition: To identify publications relevant to this review, a systematic literature search of PubMed was conducted for articles and proceedings of relevant major congresses, published between January 2010 and March 2020, reporting the use of PARP inhibitors in the treatment of cancers. Evidence synthesis: A total of 168 publications were identified, and 18 of these met the criteria for subsequent review. In addition, 15 phase 2 or on-going phase 3 (mCRPC) studies evaluating PARP inhibitors as monotherapy or in combination, which had not yet reported data, were identified through ClinicalTrials.gov. Emerging data suggest that the greatest efficacy with single-agent PARP inhibitors is seen in mCRPC patients with germline or somatic BRCA1/2 alterations (especially BRCA2 or biallelic mutations), with potential efficacy also observed in men with PALB2 and FANCA mutations. Conclusions: PARP inhibitors have demonstrated efficacy in mCRPC, and similar to ovarian and breast cancers, the greatest effect is observed in patients with HRR deficiency. The PARP inhibitors olaparib and rucaparib are now FDA approved for mCRPC patients with HRR mutations and BRCA1/2 mutations, respectively. Furthermore, when PARP inhibition is combined with novel hormonal therapies, a treatment benefit may be observed regardless of the HRR deficiency status. Gaps in the knowledge and understanding around PARP inhibitor use in prostate cancer,

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Mechanisms of resistance to PARP inhibitors - an evolving challenge in oncology

Cited by 8 publications

References 71 publications

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

Combination of Withaferin-A and CAPE Provides Superior Anticancer Potency: Bioinformatics and Experimental Evidence to Their Molecular Targets and Mechanism of Action

PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On-Going Trials

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