6533b857fe1ef96bd12b3bf7

RESEARCH PRODUCT

In the literature: June 2018

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Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a highly active family of compounds that have changed the scenario in ovarian and human epidermal growth factor receptor 2 (HER2) non-amplified breast cancer management in the recent years. Despite impressive clinical activity, a prolonged treatment with PARPi is frequently associated with acquired resistance to this therapy. The identification of mechanisms and strategies to overcome resistance are crucial. Bromodomain containing 4 (BRD4) is a member of the bromodomain and extraterminal (BET) protein family that facilitates oncogenic transcription. BRD4 is frequently amplified in high-grade serous ovarian cancer (HGSOC) and can be selectively targeted by different compounds. In a recent publication in Cancer Cell , Sun et al 1 have identified that inhibition of BRD4 (BRD4i) induced homologous recombination (HR) deficiency (HRD) sensitising tumour cells to PARPi, regardless of BRCA1/2, TP53, RAS or BRAF mutation status and reversed mechanisms of resistance to PARPi. BRD4i downregulated the DNA double-strand break (DSB) resection protein, C-terminal binding protein interacting protein (CtIP). CtIP is required to mediate DNA end resection, with loss of CtIP markedly decreasing DNA DSB repair. BRD4 inhibition induced an HRD phenotype in cells through the loss of CtIP expression. Cell damage lead by induction of DNA end resection and HRD after exposure of cells to BRDi and PARPi was dependent on CtIP expression but was not affected by BRCA1 or RAD51 ectopic expression, confirming the critical role of CtIP. The combination of BRD4i and PARPi was synergistic in most of the 55 tested cell lines. Importantly, this synergism was irrespective of ARID1A, ATM, ATR, BRCA1/2, PI3K, PTEN and TP53 mutation status. Several mechanisms of PARPi resistance have been previously described, including acquired mutations in KRAS, the restoration of BRCA WT expression through UWB1.289 BRCA-1 mutation, the …