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2017 ; 9
(400
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Repression of BET activity sensitizes homologous recombination-proficient cancers
to PARP inhibition
#MMPMID28747513
Yang L
; Zhang Y
; Shan W
; Hu Z
; Yuan J
; Pi J
; Wang Y
; Fan L
; Tang Z
; Li C
; Hu X
; Tanyi JL
; Fan Y
; Huang Q
; Montone K
; Dang CV
; Zhang L
Sci Transl Med
2017[Jul]; 9
(400
): ä PMID28747513
show ga
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 BRCA1 and RAD51, two genes essential for HR. Moreover, BETi
treatment sensitized tumors to PARP inhibition in preclinical animal models of
HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene
was focally amplified across 20 types of common cancers. Combination with BETi
could greatly expand the utility of PARP inhibition to patients with
HR-proficient cancer.
|Acetanilides/therapeutic use
[MESH]
|Animals
[MESH]
|Antineoplastic Agents/*therapeutic use
[MESH]
|Azepines/therapeutic use
[MESH]
|Benzodiazepines/therapeutic use
[MESH]
|Breast Neoplasms/drug therapy
[MESH]
|Cell Line, Tumor
[MESH]
|DNA Damage/drug effects/genetics
[MESH]
|Drug Synergism
[MESH]
|Female
[MESH]
|Heterocyclic Compounds, 3-Ring/therapeutic use
[MESH]