New BET inhibitors could overcome barriers in solid tumour treatment

New approaches to targeting BET proteins are providing renewed optimism for the treatment of solid tumours after first-generation therapies failed to deliver consistent clinical success despite encouraging early results.

A new review examines the progress made in BET inhibition, highlighting how advances in drug design and combination therapies could overcome many of the challenges that have limited the effectiveness of earlier treatments.

Early promise met with clinical challenges

BET proteins, particularly BRD4, are key in driving oncogenic transcription in solid tumours. These proteins bind to acetylated chromatin through two bromodomains, BD1 and BD2, with BRD4 recruiting P-TEFb to phosphorylate RNA polymerase II and promote the expression of cancer-driving genes such as MYC.  

Researchers found that first-generation BET inhibitors, including JQ1, molibresib and birabresib, successfully displaced BRD4 and reduced MYC expression in preclinical studies. However, these encouraging laboratory findings were not matched by widespread clinical success.  

BET proteins, particularly BRD4, are key in driving oncogenic transcription in solid tumours

Although responses were seen in patients with NUT carcinoma, where BRD4 fusions are recognised as key driver events, and in some cases of castration-resistant prostate cancer, overall efficacy remained modest. Clinical development was also hampered by short drug half-lives, dose-limiting thrombocytopenia and the emergence of treatment resistance through mechanisms including BRD4 isoform switching and activation of alternative signalling pathways such as PI3K/AKT and WNT.

Smarter therapies under development

This new review highlights several next-generation strategies designed to address these shortcomings.

BD2-selective inhibitors, including ABBV-744, have been developed to target the BD2 bromodomain while sparing BD1. This approach aims to reduce thrombocytopenia while maintaining anti-tumour activity.

Meanwhile, PROTAC degraders such as ARV-771 and MZ1 work by degrading BET proteins completely rather than simply inhibiting them. Researchers believe this strategy could overcome resistance linked to isoform switching and deliver deeper suppression of cancer-promoting pathways.

Other promising developments include bivalent inhibitors such as AZD5153, which bind both bromodomains to increase affinity, alongside dual BET/kinase and BET/HDAC inhibitors and therapies designed to disrupt BRD4-driven phase separation at super-enhancers.

Combination treatments show encouraging signs

Researchers suggest combination therapies will be essential to maximise the benefits of BET inhibition.

Studies indicate that combining BET inhibitors with PARP inhibitors may exploit DNA repair defects induced by BET inhibition, producing synergistic effects in triple-negative breast cancer and ovarian cancer. Pairing BET inhibitors with androgen receptor antagonists has also shown improved outcomes in castration-resistant prostate cancer.

Researchers suggest combination therapies will be essential to maximise the benefits of BET inhibition

Other combinations under investigation include BET inhibitors with immune checkpoint blockade, although toxicity remains a concern, as well as partnerships with HDAC and CDK inhibitors.

Clinical trials involving molibresib and birabresib have confirmed target engagement and demonstrated activity in NUT carcinoma. However, intermittent dosing schedules were required to manage thrombocytopenia. Early signs of efficacy have also emerged from combination studies involving ZEN-3694 with enzalutamide or talazoparib, although many single-agent trials have been discontinued because of limited activity, toxicity or pharmacokinetic challenges.

Focus turns to precision medicine

The review concludes that the future of BET inhibition will depend on developing more selective and degradative therapies while identifying biomarkers, including MYC amplification and BRD4 dependency, to improve patient selection.

Researchers also emphasise the importance of designing mechanism-based combination therapies, refining dosing schedules to reduce blood-related side effects and continuing to investigate rare but responsive cancers such as NUT carcinoma.

While there are still hurdles ahead, the authors conclude that next-generation BET-targeting strategies, combined with biomarker-driven clinical trials and a better understanding of resistance mechanisms, could unlock the long-term potential of BET inhibition in solid oncology.