gsk525762a and Ovarian-Neoplasms

Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azepines; Benzodiazepines; Carcinogenesis; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cell Differentiation; Cell Lineage; Cell Plasticity; Colonic Neoplasms; Disease Progression; Epigenesis, Genetic; Esophageal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Molecular Targeted Therapy; Neoplasms, Glandular and Epithelial; Neuroendocrine Tumors; Ovarian Neoplasms; Prostatic Neoplasms; Proto-Oncogene Proteins c-met; Proto-Oncogene Proteins c-myc; Pyrimidines; Retinoblastoma Binding Proteins; Triazoles; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases; Urinary Bladder Neoplasms; Uterine Cervical Neoplasms

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