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The emerging role of BET inhibitors in breast cancer.

ABSTRACT: Bromodomain and extraterminal domain (BET) proteins are epigenetic molecules that regulate the expression of multiple genes involved in carcinogenesis. Breast cancer is an heterogenous disease emerging from aberrant gene expression and epigenetic alteration patterns. Amplification or overexpression of BET proteins has been identified in breast tumors highlighting their clinical significance. Development of BET inhibitors that disrupt BET protein binding to acetylated lysine residues of chromatin and suppress transcription of various oncogenes has shown promising results in breast cancer cells and xenograft models. Currently, Phase I/II clinical trials explore safety and efficacy of BET inhibitors in solid tumors and breast cancer. Treatment-emergent toxicities have been reported, including thrombocytopenia and gastrointestinal disorders. Preliminary results demonstrated greater response rates to BET inhibitors in combination with already approved anticancer agents. Consistently, BET inhibition sensitized breast tumors to chemotherapy drugs, hormone therapy and PI3K inhibitors in vitro. This article aims to review all existing preclinical and clinical evidence regarding BET inhibitors in breast cancer.

SUBMITTER: Andrikopoulou A

PROVIDER: S-EPMC7451423 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The emerging role of BET inhibitors in breast cancer.

Andrikopoulou Angeliki A Liontos Michalis M Koutsoukos Konstantinos K Dimopoulos Meletios-Athanasios MA Zagouri Flora F

Breast (Edinburgh, Scotland) 20200813

Bromodomain and extraterminal domain (BET) proteins are epigenetic molecules that regulate the expression of multiple genes involved in carcinogenesis. Breast cancer is an heterogenous disease emerging from aberrant gene expression and epigenetic alteration patterns. Amplification or overexpression of BET proteins has been identified in breast tumors highlighting their clinical significance. Development of BET inhibitors that disrupt BET protein binding to acetylated lysine residues of chromatin ...[more]

PMID: 32827765

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Project description:Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer-olaparib and talazoparib-based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

Dataset Information

The emerging role of BET inhibitors in breast cancer.

Publications

The emerging role of BET inhibitors in breast cancer.

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