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Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities in TP53 Mutated Ultra High-Risk Neuroblastoma Cell Lines.

ABSTRACT: Most chemotherapeutics target DNA integrity and thereby trigger tumour cell death through activation of DNA damage responses that are tightly coupled to the cell cycle. Disturbances in cell cycle regulation can therefore lead to treatment resistance. Here, a comprehensive analysis of cell cycle checkpoint activation following doxorubicin (doxo) treatment was performed using flow cytometry, immunofluorescence and live-cell imaging in a panel of TP53 mutated ultra high-risk neuroblastoma (NB) cell lines, SK-N-DZ, Kelly, SK-N-AS, SK-N-FI, and BE(2)-C. Following treatment, a dose-dependent accumulation in either S- and/or G2/M-phase was observed. This coincided with a heterogeneous increase of cell cycle checkpoint proteins, i.e., phos-ATM, phos-CHK1, phos-CHK2, Wee1, p21Cip1/Waf1, and p27Kip among the cell lines. Combination treatment with doxo and a small-molecule inhibitor of ATM showed a delay in regrowth in SK-N-DZ, of CHK1 in BE(2)-C, of Wee1 in SK-N-FI and BE(2)-C, and of p21 in Kelly and BE(2)-C. Further investigation revealed, in all tested cell lines, a subset of cells arrested in mitosis, indicating independence on the intra-S- and/or G2/M-checkpoints. Taken together, we mapped distinct cell cycle checkpoints in ultra high-risk NB cell lines and identified checkpoint dependent and independent druggable targets.

SUBMITTER: Odborn Jonsson L

PROVIDER: S-EPMC8036447 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities in <i>TP53</i> Mutated Ultra High-Risk Neuroblastoma Cell Lines.

Ödborn Jönsson Linnéa L Sahi Maryam M Lopez-Lorenzo Ximena X Keller Faye Leilah FL Kostopoulou Ourania N ON Herold Nikolas N Ährlund-Richter Lars L Shirazi Fard Shahrzad S

International journal of molecular sciences 20210401 7

Most chemotherapeutics target DNA integrity and thereby trigger tumour cell death through activation of DNA damage responses that are tightly coupled to the cell cycle. Disturbances in cell cycle regulation can therefore lead to treatment resistance. Here, a comprehensive analysis of cell cycle checkpoint activation following doxorubicin (doxo) treatment was performed using flow cytometry, immunofluorescence and live-cell imaging in a panel of <i>TP53</i> mutated ultra high-risk neuroblastoma (N ...[more]

PMID: 33915913

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Project description:Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM remains highly resistant to therapy and is almost invariably fatal. The strongest genetic drivers of UM metastasis are loss-of-function mutations in tumor suppressor BAP1, an epigenetic regulator that serves as the ubiquitin hydrolase subunit of the polycomb repressive deubiquitinase (PR-DUB) complex, and a key player in global epigenetic regulation. Inactivation of BRCA Associated Protein 1 (BAP1) has been shown to induce widespread epigenetic alterations across multiple model systems. To identify novel therapeutic strategies, we investigated whether targeting the epigenome could reveal new vulnerabilities in UM. We performed high-throughput compound screening using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. Interestingly, we observed significant heterogeneity in the efficacy of different BET inhibitors in UM. While previous clinical trials with two BET inhibitors have failed to show efficacy in UM, our findings highlight substantial differences in the potency of specific BET inhibitors for this malignancy. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and completely prevented detectable metastases in the bones, spinal cord, and brain. Unexpectedly, RNA sequencing revealed a strong transcriptional overlap between BET inhibition and histone deacetylase (HDAC) inhibition-- an approach currently under clinical evaluation for UM treatment. Both BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuronal differentiation-like phenotype in UM cells. Together, our findings demonstrate that UM cells exhibit a distinct vulnerability to BET inhibition and establish BET inhibitors as promising candidates for further clinical evaluation for metastatic UM.

Dataset Information

Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities in TP53 Mutated Ultra High-Risk Neuroblastoma Cell Lines.

Publications

Heterogeneities in Cell Cycle Checkpoint Activation Following Doxorubicin Treatment Reveal Targetable Vulnerabilities in <i>TP53</i> Mutated Ultra High-Risk Neuroblastoma Cell Lines.

Similar Datasets

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