gsk525762a and Breast-Neoplasms

Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of

Topics: Animals; Breast Neoplasms; Drug Resistance, Neoplasm; Fulvestrant; Humans; MCF-7 Cells; Mice; Models, Molecular; Piperazines; Protein Domains; Pyridines; Pyridones; Receptors, Estrogen; Tissue Distribution; Transcription Factors; Xenograft Model Antitumor Assays

Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of

Topics: Acetanilides; Animals; Antineoplastic Agents; Azepines; Benzodiazepines; Breast Neoplasms; Cell Line, Tumor; DNA Damage; Drug Synergism; Female; Heterocyclic Compounds, 3-Ring; Homologous Recombination; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Triazoles

Human epidermal growth factor receptor 2 (HER2) is upregulated in a subset of human breast cancers. However, the cancer cells often quickly develop an adaptive response to HER2 kinase inhibitors. We found that an epigenetic pathway involving MLL2 is crucial for growth of HER2(+) cells and MLL2 reduces sensitivity of the cancer cells to a HER2 inhibitor, lapatinib. Lapatinib-induced FOXO transcription factors, normally tumor-suppressing, paradoxically upregulate c-Myc epigenetically in concert with a cascade of MLL2-associating epigenetic regulators to dampen sensitivity of the cancer cells to lapatinib. An epigenetic inhibitor suppressing c-Myc synergizes with lapatinib to suppress cancer growth in vivo, partly by repressing the FOXO/c-Myc axis, unraveling an epigenetically regulated FOXO/c-Myc axis as a potential target to improve therapy.

Topics: Animals; Benzodiazepines; Breast Neoplasms; Cell Line, Tumor; DNA-Binding Proteins; Drug Resistance, Neoplasm; Drug Synergism; Epigenesis, Genetic; Female; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Mice; Neoplasm Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Quinazolines; Receptor, ErbB-2; Xenograft Model Antitumor Assays

Epigenetic modifications such as histone acetylation play a central role in the transcriptional regulation of many oncogenic drivers. Accumulating evidence suggests that pharmacological modulation of certain key epigenetic reader proteins such as BRD2/3/4 may serve as an attractive strategy for treatment of many cancers, including tamoxifen-resistant breast cancer.

Topics: Acetylation; Azepines; Benzodiazepines; Breast Neoplasms; Cell Cycle Proteins; Drug Resistance, Neoplasm; Epigenesis, Genetic; Female; Histone-Lysine N-Methyltransferase; Histones; Humans; Nuclear Proteins; Protein Serine-Threonine Kinases; Receptors, Estrogen; Repressor Proteins; RNA-Binding Proteins; Tamoxifen; Transcription Factors; Triazoles