CX-5461 can destabilize replication forks in PARP inhibitor-resistant models of ovarian cancer

Xuan, Jiachen; Pearson, Richard B.; Sanij, Elaine

doi:10.1080/23723556.2020.1805256

Cited by 2 publications

(2 citation statements)

References 10 publications

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“…A phase I REPAIR trial, combining CX-5461 and the PARP inhibitor talazoparib, is underway to treat patients with metastatic castration-resistant prostate cancer (mCRPC) (ClinicalTrials.gov Identifier: NCT05425862). Initially recognized for its specific blockade of Pol I transcription by disrupting SL1-rDNA association ( 271 ), subsequent studies have unveiled that CX-5461 binds to and stabilizes G-quadruplex DNA structures, impeding replication forks and inducing DNA breaks ( 270 , 276 , 277 ). Although studies propose that the primary mechanism of CX-5461 involves topoisomerase II poisoning ( 276 ), a recent study suggested that CX-5461 primarily targets the initiation of Pol I by irreversibly inhibiting the release of RRN3 from the pre-initiation complex on the rDNA promoter.…”

Section: Targeting Ribosome Biogenesis For Cancer Therapeuticsmentioning

confidence: 99%

The impact of ribosome biogenesis in cancer: from proliferation to metastasis

Hwang,

Denicourt

2024

NAR Cancer

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The dysregulation of ribosome biogenesis is a hallmark of cancer, facilitating the adaptation to altered translational demands essential for various aspects of tumor progression. This review explores the intricate interplay between ribosome biogenesis and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal the multifaceted roles of ribosomes, extending beyond protein factories to include regulatory functions in mRNA translation. Dysregulated ribosome biogenesis not only hampers precise control of global protein production and proliferation but also influences processes such as the maintenance of stem cell-like properties and epithelial-mesenchymal transition, contributing to cancer progression. Interference with ribosome biogenesis, notably through RNA Pol I inhibition, elicits a stress response marked by nucleolar integrity loss, and subsequent G1-cell cycle arrest or cell death. These findings suggest that cancer cells may rely on heightened RNA Pol I transcription, rendering ribosomal RNA synthesis a potential therapeutic vulnerability. The review further explores targeting ribosome biogenesis vulnerabilities as a promising strategy to disrupt global ribosome production, presenting therapeutic opportunities for cancer treatment.

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Section: Targeting Ribosome Biogenesis For Cancer Therapeuticsmentioning

confidence: 99%

The impact of ribosome biogenesis in cancer: from proliferation to metastasis

Hwang,

Denicourt

2024

NAR Cancer

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“…Acetylation of histone 4 at lysine 8 (H4K8) by the histone acetyltransferase PCAF (p300/CBP-associated) recruits the MRE11 nuclease to stalled forks, but PCAF activity has been reported as low in some BRCA2-deficient cells [142]. The RNA polymerase 1 inhibitor CX-5461 has also been demonstrated to overcome replication fork protection in patient-derived xenograft (PDX) models of HRR-deficient HGSOC involving MRE11 degradation of replication forks [143,144]. Down-regulation of the de-ubiquitylating enzyme USP1 (ubiquitin specific peptidase 1) in BRCA1-deficient cells leads to replication fork destabilisation in a synthetic lethal manner and may be another strategy to address PARPi resistance in HRR deficient tumour cells that have undergone stabilisation of the DNA replication fork [145,146].…”

Section: Stabilisation/destabilisation Of the Dna Replication Forkmentioning

confidence: 99%

Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival

Xie

Dickson

Yee

et al. 2022

Cancers

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The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% displaying defective HRR. Poly ADP ribose polymerases (PARPs) are a family of enzymes that catalyse the transfer of ADP-ribose to target proteins, functioning in fundamental cellular processes including transcription, chromatin remodelling and DNA repair. In cells with deficient HRR, PARP inhibitors (PARPis) cause synthetic lethality leading to cell death. Despite the major advances that PARPis have heralded for women with ovarian cancer, questions and challenges remain, including: can the benefits of PARPis be brought to a wider range of women with ovarian cancer; can other drugs in clinical use function in a similar way or with greater efficacy than currently clinically approved PARPis; what can we learn from long-term responders to PARPis; can PARPis sensitise ovarian cancer cells to immunotherapy; and can synthetic lethal strategies be employed more broadly to develop new therapies for women with ovarian cancer. We examine these, and other, questions with focus on improving outcomes for women with ovarian cancer.

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CX-5461 can destabilize replication forks in PARP inhibitor-resistant models of ovarian cancer

Cited by 2 publications

References 10 publications

The impact of ribosome biogenesis in cancer: from proliferation to metastasis

The impact of ribosome biogenesis in cancer: from proliferation to metastasis

Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival

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