F-Box Protein-Mediated Resistance to PARP Inhibitor Therapy

Adamovich, Aleksandra I.; Toland, Amanda E.; Parvin, Jeffrey D.

doi:10.1016/j.molcel.2018.12.019

Cited by 4 publications

(6 citation statements)

References 11 publications

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“…It had been predicted that combined effects of CHK1i and PARPi would restore sensitivity of cells that had reduced EMI1 expression levels [8,20]. Results presented in this study confirm this notion for BRCA1-mutant breast cancer cells.…”

Section: Plos Onesupporting

confidence: 78%

“…Despite the promising preliminary results, prolonged treatment of breast or ovarian cancer with PARPi is frequently associated with acquired resistance to this therapy. There are multiple mechanisms of resistance to PARPi chemotherapy, some of them are targetable for therapy including the modulation of EMI1 and RAD51 expression levels [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells

et al. 2021

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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. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell 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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Section: Plos Onesupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells

et al. 2021

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show abstract

“…It had been predicted that combined effects of CHK1i and PARPi would restore sensitivity of cells that had reduced EMI1 expression levels (8,20). Results presented in this study confirm this notion for BRCA1-mutant breast cancer cells.…”

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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“…In PARPi resistant cells, RAD51 levels are elevated due to the downregulation of EMI1, a mitotic regulator that assembles a ubiquitin ligase complex involved in RAD51 degradation [89]. Therefore, EMI1 downregulation allows the accumulation of RAD51, which may facilitate HR and PARPi resistance [90].…”

Section: Promotion Of Repair Protein Recruitmentmentioning

confidence: 99%

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Lee

Matulonis

2020

Cancers

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The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

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F-Box Protein-Mediated Resistance to PARP Inhibitor Therapy

Cited by 4 publications

References 11 publications

Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells

Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells

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

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

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