Reverse the Resistance to PARP Inhibitors

Kim, Yevgeniy; Kim, Aleksei; Sharip, Ainur; Sharip, Aigul; Jiang, Juhong; Yang, Qing; Xie, Yingqiu

doi:10.7150/ijbs.17240

Cited by 69 publications

(43 citation statements)

References 119 publications

(184 reference statements)

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“…For this reason we were able to identify two additional tumor cases with mutations in other DNA damage response genes than BRCA1/2 (PALB2 and NBN), which might also respond to PARP-inhibitor therapy. BRCA1/ 2-mutated ovarian cancers respond to platinum-based chemotherapy and PARP-inhibition therapy and current studies further investigate the effect of PARP-inhibition both on other cancer entities and on cancers driven by pathogenic mutations in other DDR-genes [37][38][39]. With regards to this, detection of SNVs and CNVs in a larger number of genes becomes increasingly important.…”

Section: Discussionmentioning

confidence: 99%

Targeted capture-based NGS is superior to multiplex PCR-based NGS for hereditary BRCA1 and BRCA2 gene analysis in FFPE tumor samples

et al. 2019

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Background: With the introduction of Olaparib treatment for BRCA-deficient recurrent ovarian cancer, testing for somatic and/or germline mutations in BRCA1/2 genes in tumor tissues became essential for treatment decisions. In most cases only formalin-fixed paraffin-embedded (FFPE) samples, containing fragmented and chemically modified DNA of minor quality, are available. Thus, multiplex PCR-based sequencing is most commonly applied in routine molecular testing, which is predominantly focused on the identification of known hot spot mutations in oncogenes. Methods: We compared the overall performance of an adjusted targeted capture-based enrichment protocol and a multiplex PCR-based approach for calling of pathogenic SNVs and InDels using DNA extracted from 13 FFPE tissue samples. We further applied both strategies to seven blood samples and five matched FFPE tumor tissues of patients with known germline exon-spanning deletions and gene-wide duplications in BRCA1/2 to evaluate CNV detection based solely on panel NGS data. Finally, we analyzed DNA from FFPE tissues of 11 index patients from families suspected of having hereditary breast and ovarian cancer, of whom no blood samples were available for testing, in order to identify underlying pathogenic germline BRCA1/2 mutations. Results: The multiplex PCR-based protocol produced inhomogeneous coverage among targets of each sample and between samples as well as sporadic amplicon drop out, leading to insufficiently or non-covered nucleotides, which subsequently hindered variant detection. This protocol further led to detection of PCR-artifacts that could easily have been misinterpreted as pathogenic mutations. No such limitations were observed by application of an adjusted targeted capture-based protocol, which allowed for CNV calling with 86% sensitivity and 100% specificity. All pathogenic CNVs were confirmed in the five matched FFPE tumor samples from patients carrying known pathogenic germline mutations and we additionally identified somatic loss of the second allele in BRCA1/2. Furthermore we detected pathogenic BRCA1/2 variants in four the eleven FFPE samples from patients of whom no blood was available for analysis. Conclusions: We demonstrate that an adjusted targeted capture-based enrichment protocol is superior to commonly applied multiplex PCR-based protocols for reliable BRCA1/2 variant detection, including CNV-detection, using FFPE tumor samples.

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Section: Discussionmentioning

confidence: 99%

Targeted capture-based NGS is superior to multiplex PCR-based NGS for hereditary BRCA1 and BRCA2 gene analysis in FFPE tumor samples

et al. 2019

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“…Epigenetic reexpression of BRCA1, BRCA1 deletion isoforms, genetic reversion of BRCA, or replication machinery stabilization may partially restore the HR molecular pathway and mediate PARPi resistance. Additionally, researchers showed that several miRNAs could induce PARPi resistance via balancing NHEJ and DSB repair pathways or by suppressing HR repair proteins (43). Here, we demonstrated that let-7e decreased the expression of BRCA1 and Rad51 and suppressed DSB repairs through targeting PARP1.…”

Section: Discussionmentioning

confidence: 61%

Let-7e Suppresses DNA Damage Repair and Sensitizes Ovarian Cancer to Cisplatin through Targeting PARP1

Xiao

Guo

Xie

et al. 2020

Molecular Cancer Research

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Increased DNA damage repair is one of the mechanisms implicated in cisplatin resistance. Our previous study indicated that the deregulation of let-7e promoted cisplatin resistance and that let-7e could suppress DNA double-strand break repair in ovarian cancer. In this study, we further characterized the role of let-7e in DNA damage repair and cisplatin resistance in ovarian cancer, and investigated the underlying mechanisms. The alkaline and neutral comet assay indicated that let-7e impeded both DNA single-and double-strand break repairs through downregulating its target gene PARP1. In vitro and in vivo experiments provided evidence that the let-7e-PARP1-DNA repair axis was involved in the modulation of cisplatin sensitivity in ovarian cancer. Contrary to let-7e, PARP1 was overexpressed in cisplatin-resistant ovarian cancer tissues, and patients with high PARP1 expression exhibited poor progressionfree survival (PFS) and overall survival (OS). Multivariate logistic and Cox regression analyses showed that let-7e and FIGO stage were independent prognostic factors for PFS and OS, whereas let-7e and PARP1 were able to independently predict chemotherapy response. Taken together, our results indicated that low expression of let-7e promoted DNA single-and double-strand break repairs and subsequently contributed to cisplatin resistance by relieving the suppression on PARP1 in ovarian cancer. Implications: Targeting the let-7e-PARP1-DNA repair axis might be an effective strategy for the treatment of chemoresistant ovarian cancer.

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“…It is well established that the "BRCAness" phenotype of the breast cancer cells plays a crucial role toward PARPi sensitivity and conferring the concept of synthetic lethality, and our results are consistent with that concept. Partial restoration of the homologous recombination DNA repair pathway can lead to resistance to PARPi (27), and upregulation of RAD51 in BRCA1defective cells is associated with resistance to PARPi (20). It is worth noting that our results of olaparib resistance in different BRCA1 mutant cells due to EMI1 downregulation that were associated with high RAD51 levels are in line with previous results done either in BRCA1 mutant cancer cells (20) or BRCA2 mutant ones (25).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Early Mitotic Inhibitor 1 (EMI1) Depletion on the Sensitivity of PARP Inhibitors in BRCA1 Mutated Triple-Negative Breast Cancer Cells

Parvin

Moustafa

Elwahed

et al. 2020

Preprint

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Triple negative breast cancer (TNBC) represents approximately 10-15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Surprisingly, EMI1 depletion also led to resistance to a MEK inhibitor, though this inhibitor blocks cells in G1 phase of the cell cycle and would not be expected to be sensitive to EMI1 levels. Notably, increasing the RAD51 protein expression only partially recapitulated the effects of EMI1 depletion in causing resistance to different PARPi and the other cytotoxic drugs.These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells.

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Reverse the Resistance to PARP Inhibitors

Cited by 69 publications

References 119 publications

Targeted capture-based NGS is superior to multiplex PCR-based NGS for hereditary BRCA1 and BRCA2 gene analysis in FFPE tumor samples

Targeted capture-based NGS is superior to multiplex PCR-based NGS for hereditary BRCA1 and BRCA2 gene analysis in FFPE tumor samples

Let-7e Suppresses DNA Damage Repair and Sensitizes Ovarian Cancer to Cisplatin through Targeting PARP1

Modulation of Early Mitotic Inhibitor 1 (EMI1) Depletion on the Sensitivity of PARP Inhibitors in BRCA1 Mutated Triple-Negative Breast Cancer Cells

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