A unified mechanism for PARP inhibitor-induced PARP1 chromatin retention at DNA damage sites in living cells

Kanev, Petar-Bogomil; Varhoshkova, Sylvia; Georgieva, Irina; Lukarska, Maria; Kirova, Dilyana; Danovski, Georgi; Stoynov, Stoyno; Aleksandrov, Radoslav

doi:10.1016/j.celrep.2024.114234

Cell Reports

2024

DOI: 10.1016/j.celrep.2024.114234

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A unified mechanism for PARP inhibitor-induced PARP1 chromatin retention at DNA damage sites in living cells

Petar-Bogomil Kanev,

Sylvia Varhoshkova,

Irina Georgieva

et al.

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2024

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Cited by 8 publications

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Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer

MacGilvary,

Cantor

2024

DNA Repair

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Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer

MacGilvary,

Cantor

2024

DNA Repair

View full text Add to dashboard Cite

Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition

Lin,

Soni,

Hessenow

et al. 2024

Radiotherapy and Oncology

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Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms

Jain,

Barge,

Parris

2024

Oncogene

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Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer’s intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.

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A unified mechanism for PARP inhibitor-induced PARP1 chromatin retention at DNA damage sites in living cells

Cited by 8 publications

References 87 publications

Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer

Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer

Talazoparib enhances resection at DSBs and renders HR-proficient cancer cells susceptible to Polθ inhibition

Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms

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