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The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

SUBMITTER: Moens S

PROVIDER: S-EPMC7862668 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.

Moens Stijn S Zhao Peihua P Baietti Maria Francesca MF Marinelli Oliviero O Van Haver Delphi D Impens Francis F Floris Giuseppe G Marangoni Elisabetta E Neven Patrick P Annibali Daniela D Sablina Anna A AA Amant Frédéric F

Scientific reports 20210204 1

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based ...[more]

PMID: 33542435

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Project description:Triple-negative breast cancer (TNBC) stands out as a particularly aggressive and frequently recurring form of breast cancer. Due to the absence of hormone receptors, the available treatment avenues are constrained, making chemotherapy the primary approach. Unfortunately, the development of resistance to chemotherapy poses a significant challenge, further restricting the already limited therapeutic alternatives for recurrent cases. Understanding the molecular basis of chemotherapy resistance in TNBC is pivotal for improving treatment outcomes. Here, we generated two different Taxol-resistant TNBC cell lines with dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited hallmark features of resistance, including reduced cell growth, altered morphology, and resistance to apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in the resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted epigenome-wide CRISPR/Cas9 and chemical probe library screens. Both screens pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) which is the reader protein in MOZ/MORF histone acetyl-transferase complex, as the regulator of Taxol resistance in TNBC cells. Knockout of BRPF1, but not the other members of the MOZ/MORF complex, sensitized resistant cells to Taxol. Additionally, BRPF1 inhibitors, PFI-4 and OF-1, in combination with Taxol significantly reduced cell viability. Transcriptome analysis upon BRPF1 loss or inhibition revealed a negative impact on ribosome biogenesis-related gene sets, resulting in a global decrease in protein translation in Taxol-resistant cells. Our ChIP-qPCR analysis further demonstrated that active BRPF1 directly interacts with the ABCB1 promoter, enhancing its expression and inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. This dual mechanism critically sensitizes Taxol-resistant TNBC cells to chemotherapy. Our findings uncover a comprehensive molecular framework, highlighting the pivotal role of epigenetic reader protein BRPF1 in Taxol resistance and providing potential avenues for therapeutic intervention in TNBC.

Dataset Information

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.

Publications

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers.

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