rvx-208 and Breast-Neoplasms

BRCA1 is a tumor suppressor frequently mutated in breast and ovarian cancer, serving it as a target for therapeutic exploitation. Here, we show that BRCA1 has a synthetic lethality interaction with an epigenetics regulator, bromodomain and extra-terminal domain (BET). BET inhibition led to gene expression changes reversing MYC-dependent transcription repression of a redox regulator, thioredoxin-interacting protein (TXNIP), via switching the promoter occupant from MYC to MondoA:MLX complex. Reversing the MYC-TXNIP axis inhibited thioredoxin activity and elevated cellular oxidative stress, causing DNA damages that are detrimental to BRCA1-deficient breast cancer cells. Tumor xenograft models and breast cancer clinical data analyses further demonstrated an in vivo synthetic lethality interaction and clinical association between BET/TXNIP and BRCA1 deficiency in the survival of breast cancer patients.

Topics: Animals; Apoptosis; BRCA1 Protein; Breast Neoplasms; Carrier Proteins; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Genes, BRCA1; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Proteins; Quinazolinones; Xenograft Model Antitumor Assays

Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 9f induced ACD pathways involved in HMGB1, VDAC1/2, and eEF2. Moreover, 9f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Autophagy; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Embryo, Nonmammalian; Female; Humans; Mice, Inbred BALB C; Molecular Docking Simulation; Nuclear Proteins; Small Molecule Libraries; Structure-Activity Relationship; Transcription Factors; Xenograft Model Antitumor Assays; Zebrafish