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

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. What's new? A new combination therapy shows promise against non‐small cell lung cancer (NSCLC). Inhibitors of bromodomain and extraterminal domain (BET) proteins act against various cancers, including NSCLC. Here, the authors investigated the combined effect of BET inhibitors with inhibitors of the tyrosine kinase WEE1. Combined inhibition of BET and WEE1 harms NSCLC in two ways. First, it stifles the non‐homologous end joining mechanism of DNA double‐strand break repair. Furthermore, it forces progression of the cell cycle into mitosis, despite the unrepaired DNA damage, leading to apoptosis. This is the first report to show synergistic action between these two types of inhibitors.