Targeting of RecQ Helicases as a Novel Therapeutic Strategy for Ovarian Cancer

Maity, Jyotirindra; Horibata, Sachi; Zurcher, Grant; Lee, Jungmin

doi:10.3390/cancers14051219

Cited by 7 publications

(10 citation statements)

References 101 publications

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“…BLM is a member of the RecQ helicase family, which is critical for replication fork stability by unwinding structures, such as G-quadruplex and Holliday junctions, for DNA replication ( 34 ). BLM also helps restart the stalled forks while suppressing the firing of new origins in response to replication stress ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancer

et al. 2023

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Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ( BRCA )–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase ( BLM ) and cyclin E1 ( CCNE1 ) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork–related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA -mutant HGSC.

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Section: Resultsmentioning

confidence: 99%

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancer

et al. 2023

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“…Inhibition of BLM may affect DNA stability and the DDR pathway. ML216, an inhibitor of BLM, modulates the role of BLM in genome maintenance in human cells and increases the frequency of SCEs [ 45 ]. Another inhibitor of BLM compound 9h could effectively disrupt BLM recruitment to DNA in cells and trigger DDR at the telomere region [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Bloom’s Syndrome Protein (BLM) Inhibitor Suppressing Growth and Metastasis of Prostate Cancer

Zhao

et al. 2022

IJMS

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Prostate cancer (PCa) is a common cancer and a major cause of cancer-related death worldwide in men, necessitating novel targets for cancer therapy. High expression of Bloom’s syndrome protein (BLM) helicase is associated with the occurrence and development of PCa. Therefore, the identification and development of new BLM inhibitors may be a new direction for the treatment of PCa. Here, we identified a novel inhibitor by molecular docking and put it to systematic evaluation via various experiments, AO/854, which acted as a competitive inhibitor that blocked the BLM-DNA interaction. Cellular evaluation indicated that AO/854-suppressed tumor growth and metastasis in PC3 cells by enhancing DNA damage, phosphorylating Chk1/Chk2, and altering the p53 signaling pathway. Collectively, the study highlights the potential of BLM as a therapeutic target in PCa and reveals a distinct mechanism by which AO/854 competitively inhibits the function of BLM.

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“… Source: Guo et al ., 39 Maity et al ., 40 Christie et al . 41 * PDX #183 was a chemo-naïve platinum-sensitive HGSC PDX model included as a comparator for PDX platinum response.…”

Section: Methodsmentioning

confidence: 99%

The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models

Ho,

Vandenberg,

Lim

et al. 2023

Ther Adv Med Oncol

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Background: Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease. Objectives: To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC. Design and methods: Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 ( BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken. Results: Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1. Conclusion: The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.

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Targeting of RecQ Helicases as a Novel Therapeutic Strategy for Ovarian Cancer

Cited by 7 publications

References 101 publications

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancer

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor–resistant BRCA -mutant ovarian cancer

Discovery of a Novel Bloom’s Syndrome Protein (BLM) Inhibitor Suppressing Growth and Metastasis of Prostate Cancer

The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models

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