Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity

Heijink, Anne Margriet; Everts, Maaike; Honeywell, Megan E.; Richards, Ryan; Kok, Yannick P; Vries, Elisabeth G.E. de; Lee, Michael J.; Vugt, Marcel A.T.M. van

doi:10.1016/j.celrep.2019.07.070

Cited by 31 publications

(27 citation statements)

References 48 publications

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“…Notably, cisplatin does not initially cause replication forks to stall and collapse (Huang et al, 2013;Mutreja et al, 2018). Moreover, recent findings indicate that cisplatin toxicity in triple negative breast cancer is unrelated to loss of DNA repair factors (Heijink et al, 2019). In addition, in several distinct models restored FP fails to restore cisplatin resistance, suggesting FP is uncoupled from the mechanism of resistance (Feng and Jasin, 2017) (Cantor and Calvo, 2018).…”

mentioning

confidence: 99%

Replication gaps underlie BRCA-deficiency and therapy response

Panzarino

Krais

Peng

et al. 2019

Preprint

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Cancers that are deficient in BRCA1 or BRCA2 are hypersensitive to genotoxic agents, including platinums and other first-line chemotherapeutics. The established models propose that these cancers are hypersensitive because the chemotherapies block or degrade DNA replication forks and thereby create DNA double strand breaks, both of which require functional BRCA proteins to prevent or resolve by mechanisms termed fork protection (FP) or homologous recombination (HR). However, recent findings challenge this dogma because genotoxic agents do not initially cause DNA double strand breaks or stall replication forks. Here, we propose a new model for genotoxic chemotherapy in which ssDNA replication gaps underlie the hypersensitivity of BRCA deficient cancer, and we propose that defects in HR or FP do not. Specifically, we observed that ssDNA gaps develop in BRCA deficient cells because DNA replication is not effectively restrained in response to genotoxic stress. Moreover, we observe gap suppression (GS) by either restored fork restraint or by gap filling, both of which conferred resistance to therapy in tissue culture and BRCA patient tumors. In contrast, restored HR and FP were not sufficient to prevent hypersensitivity if ssDNA gaps were not eliminated. Together, these data suggest that ssDNA replication gaps underlie the BRCA cancer phenotype, "BRCAness," and we propose are fundamental to the mechanism of action of genotoxic chemotherapies. Introduction:Mutations in the hereditary breast cancer genes, BRCA1 and BRCA2, first demonstrated that cancer is a genetic disease in which susceptibility to cancer could be inherited (King et al., 1986). In addition to breast cancer, mutated BRCA1 or BRCA2 also cause a predisposition to other cancer types, including breast, ovarian, pancreatic, and colorectal cancers. Importantly, cancers with mutated BRCA genes are hypersensitive to cisplatin, a first-line anti-cancer chemotherapy that has been the standard of care for ovarian cancer for over 40 years (Munnell, 1968). BRCA deficient cancers are thought to be

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mentioning

confidence: 99%

Replication gaps underlie BRCA-deficiency and therapy response

Panzarino

Krais

Peng

et al. 2019

Preprint

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“…Those functions are attributed to the RRM and the NTF2 protein domains [ 65 , 66 ], which are also essential for SGs formation [ 22 ]. G3BP1 and G3BP2 have been linked to chemo- and radio-resistance [ 69 , 70 ], as their depletions in cell lines increase treatment efficiency. Ultimately, two studies investigated the role of G3BP1 in cancer development in in vivo experiments.…”

Section: Sgs Regulators and Their Role In Cancermentioning

confidence: 99%

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

Aulas

Finetti

Lyons

et al. 2020

Cancers

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Cancer treatments are constantly evolving with new approaches to improve patient outcomes. Despite progresses, too many patients remain refractory to treatment due to either the development of resistance to therapeutic drugs and/or metastasis occurrence. Growing evidence suggests that these two barriers are due to transient survival mechanisms that are similar to those observed during stress response. We review the literature and current available open databases to study the potential role of stress response and, most particularly, the involvement of Stress Granules (proteins) in cancer. We propose that Stress Granule proteins may have prognostic value for patients.

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“…Platinum compounds, including carboplatin and cisplatin, exert their cytotoxic effect by introducing DNA crosslinks, which halt the replication fork (Heijink et al, 2019). These agents have been for a long time an unfavorable option in breast cancer due to the availability of other less toxic agents that are also easier in administration (González-Neira, 2012).…”

Section: Platinum Compoundsmentioning

confidence: 99%

“…These agents have been for a long time an unfavorable option in breast cancer due to the availability of other less toxic agents that are also easier in administration (González-Neira, 2012). More recent evidence about the superior benefit of these agents over other cytotoxic drugs in triple-negative BC patients with BRCA1/2 mutations brought back these old drugs under focus (Heijink et al, 2019).…”

Section: Platinum Compoundsmentioning

confidence: 99%

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

2020

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Breast cancer (BC) is one of the most prevalent types of cancer worldwide with high morbidity and mortality rates. Treatment modalities include systemic therapy, in which chemotherapy is a major component in many cases. Several chemotherapeutic agents are used in combinations or as single agents with many adverse events occurring in variable frequencies. These events can be a significant barrier in completing the treatment regimens. Germline genomic variants are thought of as potential determinants in chemotherapy response and the development of side effects. Some pharmacogenomic studies were designed to explore germline variants that can be used as biomarkers for predicting developing toxicity or adverse events during chemotherapy in BC. In this review, we reassess and summarize the major findings of pharmacogenomic studies of chemotherapy toxicity during BC management. In addition, deficiencies hampering utilizing these findings and the potential targets of future research are emphasized. Main insufficiencies in toxicity pharmacogenomics studies originate from study design, sample limitations, heterogeneity of selected genes, variants, and toxicity definitions. With the advent of high throughput genotyping techniques, researchers are expected to explore the identified as well as the potential genetic biomarkers of toxicity and efficacy to improve BC management. However, to achieve this, the limitations of previous work should be evaluated and avoided to reach more conclusive and translatable evidence for personalizing BC chemotherapy.

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Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity

Cited by 31 publications

References 48 publications

Replication gaps underlie BRCA-deficiency and therapy response

Replication gaps underlie BRCA-deficiency and therapy response

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

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