Repression of BET activity sensitizes homologous recombination–proficient cancers to PARP inhibition

Yang, Lu; Zhang, Youyou; Shan, Weiwei; Hu, Zhongyi; Yuan, Jiao; Pi, Jingjiang; Wang, Yueying; Fan, Lingling; Tang, Zhaoqing; Li, Chunsheng; Hu, Xiaowen; Tanyi, János L.; Fan, Yi; Huang, Qihong; Montone, Kathleen T.; Dang, Chi V.; Zhang, Lin

doi:10.1126/scitranslmed.aal1645

Cited by 187 publications

(206 citation statements)

References 63 publications

(150 reference statements)

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“…Consistently, JQ1 also impaired the formation of RAD51 foci induced by ionizing radiation (Figure 3D–E) and reduced the HR efficacy as determined by the direct-repeat-GFP reporter assay (Figure 3F). Similar to a recent publication (Yang et al, 2017), JQ1 decreased the expression of BRCA1 and RAD51 levels (Figure S2D–E). Compared with Olaparib alone, knockdown of WEE1 and TOPBP1 expression decreased the levels of phosphorylated CHK1, increased γH2AX and impaired RAD51 foci formation when combined with Olaparib (Figure 3G–H and S2F–G).…”

Section: Resultssupporting

confidence: 90%

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BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

et al. 2017

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Summary PARP inhibition is known to be an effective clinical strategy in BRCA-mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here we show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell cycle checkpoint regulator WEE1 and the DNA damage response factor TOPBP1. When combined with the PARP inhibitor Olaparib, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.

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Section: Resultssupporting

confidence: 90%

“…Changes in the expression of other genes could also contribute to the observed synergy. Indeed, a recent study showed that BET inhibitors reduce HR activity (Yang et al, 2017). In addition, BRD4 may regulate distal enhancer activity in addition to promoter activity (Shi and Vakoc, 2014).…”

Section: Discussionmentioning

confidence: 99%

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

et al. 2017

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“…Although the effect of BET inhibitors on the expression of oncogenes such as c‐Myc has been extensively addressed, the mechanisms by which BET inhibition produces cytotoxicity remain unknown. However, several recent studies have reported that BRD4 is essential for the repair of DNA double‐strand breaks (DSBs), and that BET inhibitors suppress both of the major DSB repair mechanisms, homologous recombination (HR) and nonhomologous end joining (NHEJ) …”

Section: Introductionmentioning

confidence: 99%

Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

Takashima

Kikuchi

et al. 2019

Intl Journal of Cancer

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Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET‐inhibiting drugs on the expression of oncogenes such as c‐Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2‐M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775‐induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775‐induced DNA double‐strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET‐inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.

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“…These proteins are found to be highly amenable for small molecules and numerous chemical inhibitors have been developed to target a number of bromodomains. Among these, inhibitors of BRD4 were recently shown to potently inhibit HR efficiency in many different types of cancer cells, including breast cancer, ovarian cancer and pancreatic cancer [12,13]. Different mechanisms have been proposed for how the BRD4 inhibitors inhibit HR.…”

Section: Transcriptional Regulationmentioning

confidence: 99%

“…Different mechanisms have been proposed for how the BRD4 inhibitors inhibit HR. One mechanism involves the transcription repression of BRCA1 and Rad51 [12] by BRD4 inhibitors, while another is through transcription inhibition of CtIP [13], whose gene product enhances the MRN complex's nuclease activity to process the DSB sites to initiate HR. It is possible that different chromatin states in different cell types may favor one mechanism over the other.…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Drugging Homologous Recombination: Back to the Future

2018

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If a person is lucky to live long enough, he/she will also have a significantly increased likelihood of developing a cancer. Cancer is caused by accumulation of gene mutations over time. Genomic instability is one of the two key enabling characteristics of cancer cells [1], first enabling initial tumorigenesis and later drug resistance. Genomic stability is critical to maintain cellular homeostasis and cellular identity. However, cellular DNA is constantly under the attack from both endogenous and exogenous threats, creating lesions. These lesions, particularly the DNA double-strand breaks (DSBs) are lethal to the cells. They must be repaired for the cells to survive and proliferate. There are two major pathways to repair the DSBs in mammalian cells. One is error-free homologous recombination repair (HR) and the other one is error-prone nonhomologous end-joining repair [2]. During HR, a homologous sister chromatin is used as a template to repair the breaks. In nonhomologous end-joining, on the other hand, the broken DNA ends are simply ligated together without a need for a homologous template, often leading to some deletions of the original DNA sequences. It is the HR process that maintains the integrity of our cellular genome. Reversing resistanceWhile genomic instability is a hallmark of cancer cells, the genome cannot be too unstable. After passing a certain intolerable threshold, the cancer cells will die from excessive DSBs or genomic changes. This creates a unique opportunity to develop novel cancer therapies by targeting the HR pathway. The viability of targeting HR repair for anti-cancer therapeutics is supported by the recent US FDA approval of three different PARP inhibitors (olaparib, rucaparib and niraparib) for high-grade serous ovarian cancer (HGSOC). These PARP inhibitors are mostly effective in patients with preexisting somatic or germline BRCA mutations through a process called synthetic lethality [3]. BRCA1 and BRCA2 are two distinct breast and ovarian cancer-associated tumor suppressor genes. They are essential for instigating the HR repair pathway in collaboration with the nuclease MRN (Mre11-Rad50-NBS1) complex [2]. Mutations in BRCA genes result in deficient HR repair activity, a process which cancer cells are particularly reliant on due to high level of replication stress [4]. In the case of HGSOC, carriers of BRCA, which account for only approximately 30% of the patients are more sensitive to existing drugs including platinum salts and PARP inhibitors present significantly better prognosis than noncarriers. Even these BRCA carriers eventually develop resistance to the PARP inhibitors or platinum drugs. Although the mechanisms underlying the resistance are incompletely understood, restoration of HR function is a major cause [5,6]. Therefore, pharmacological strategies to drug the HR pathway can potentially expand the utility of existing PARP inhibitors and platinum drugs by priming the non-BRCA carriers and reversing the resistance mechanisms seen in the clinic with PARP inhibitors and pla...

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Repression of BET activity sensitizes homologous recombination–proficient cancers to PARP inhibition

Cited by 187 publications

References 63 publications

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer

Bromodomain and extraterminal domain inhibition synergizes with WEE1‐inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

Drugging Homologous Recombination: Back to the Future

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