gsk-2816126 and Breast-Neoplasms

The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype.. Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-deficient and -proficient mouse mammary tumors.. We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors.. Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; BRCA1 Protein; Breast Neoplasms; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Indoles; Mammary Neoplasms, Experimental; Mice; Protein Kinase Inhibitors; Pyridones; Synthetic Lethal Mutations

Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Doxycycline; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Female; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Histones; Humans; Indoles; Lung Neoplasms; Mice; Mice, Knockout; Molecular Targeted Therapy; Protein Processing, Post-Translational; Pyridones; Signal Transduction; Transcription, Genetic; Xenograft Model Antitumor Assays