Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

Abstract

In gastrointestinal stromal tumours (GISTs), the function of bromodomain‐containing 4 (BRD4) remains underexplored. BRD4 mRNA abundance was quantified in GISTs. In the current study, we investigated the role of BRD4 in GISTs. Our results show a significant enhancement in BRD4 mRNA and a shift from very low‐risk/low‐risk to high‐risk levels as per NCCN specifications. Overexpression of BRD4 correlated with unfavourable genotype, nongastric location, enhanced risk and decreased disease‐free survival, which were predicted independently. Knockout of BRD4 in vitro suppressed KIT expression, which led to inactivation of the KIT/PI3K/AKT/mTOR pathway, impeded migration and cell growth and made the resistant GIST cells sensitive to imatinib. The expression of KIT was repressed by a BRD4 inhibitor JQ1, which also induced myristoylated‐AKT‐suppressible caspases 3 and 9 activities, induced LC3‐II, exhibited dose‐dependent therapeutic synergy with imatinib and attenuated the activation of the PI3K/AKT/mTOR pathway. In comparison with their single therapy, the combination of JQ1/imatinib more efficiently suppressed the growth of xenografts and exhibited a reduction in KIT phosphorylation, a decrease in Ki‐67 and in the levels of phosphorylated PI3K/AKT/mTOR and enhanced TUNEL staining. Thus, we characterized the biological, prognostic and therapeutic implications of overexpressed BRD4 in GIST and observed that JQ1 suppresses KIT transactivation and nullifies the activation of PI3K/AKT/mTOR, providing a potential strategy for treating imatinib‐resistant GIST through dual blockade of KIT and BRD4.

BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1

“…In our study, we observed that BET inhibition exhibited two independent downstream effects in CRC cells, including MYC repression and AKT inhibition. AKT inhibition by BETi is consistent with previous reports, showing that BETi repressed RTK expression and subsequently inactivated PI3K/AKT pathway 36,37 . Since RTKs serve as an upstream activator of PI3K/AKT, inhibition of AKT phosphorylation by BETi is likely to be attributed to the blockade of RTK expression, such as EGFR family and KIT.…”

BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1

“…In our study, we observed that BET inhibition exhibited two independent downstream effects in CRC cells, including MYC repression and AKT inhibition. AKT inhibition by BETi is consistent with previous reports, showing that BETi repressed RTK expression and subsequently inactivated PI3K/AKT pathway 35 , 36 . Since RTKs serve as an upstream activator of PI3K/AKT, inhibition of AKT phosphorylation by BETi is likely to be attributed to the blockade of RTK expression, such as EGFR family and KIT.…”

THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours

“…Several core transcription factors have been revealed to play essential roles in driving GIST cell proliferation and metastasis by binding to enhancers of GISTassociated genes and facilitating KIT gene expression [13][14][15]. Moreover, a previous study revealed that the KIT-regulated enhancer domain in GISTs could be targeted by BRD4, a key activator of RNAPII transcription at active chromatin marks, and the BET bromodomain inhibitor (BBI) can downregulate KIT transcription [34,35]. Therefore, characterization of transcription factor deregulation in GIST may provide innovative insights into the pathogenesis mechanisms and offer new therapeutic approaches.…”