The battle against solid tumours is far from over, but a new wave of BET inhibitors and combination therapies is offering renewed hope. While first-generation BET inhibitors showed promise in preclinical studies, their clinical translation fell short. However, the development of BD2-selective inhibitors, PROTAC degraders, and biomarker-driven combination strategies is paving the way for more effective treatments. These next-generation therapies aim to address the limitations of earlier approaches, offering a glimmer of optimism for patients and researchers alike.
One of the key challenges with first-generation BET inhibitors was their inability to consistently translate preclinical success into clinical benefit. This was partly due to the broad targeting of BET proteins, which led to off-target effects and limited efficacy. For instance, while responses were observed in patients with NUT carcinoma, where BRD4 fusions are a significant driver, the overall efficacy was modest. Additionally, short drug half-lives, dose-limiting thrombocytopenia, and the emergence of treatment resistance through mechanisms like BRD4 isoform switching and alternative signalling pathways hindered clinical development.
To overcome these hurdles, researchers are now focusing on more targeted and degradative therapies. BD2-selective inhibitors, such as ABBV-744, are designed to target the BD2 bromodomain while sparing the BD1 domain. This approach aims to reduce thrombocytopenia, a common side effect, while maintaining anti-tumour activity. PROTAC degraders, like ARV-771 and MZ1, take a different approach by completely degrading BET proteins, which could overcome resistance linked to isoform switching and deliver deeper suppression of cancer-promoting pathways.
Combination therapies are also emerging as a powerful strategy 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 shown improved outcomes in castration-resistant prostate cancer. 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.
The future of BET inhibition in solid oncology will depend on several key factors. Firstly, developing more selective and degradative therapies is crucial. This includes refining dosing schedules to reduce blood-related side effects and identifying biomarkers, such as MYC amplification and BRD4 dependency, to improve patient selection. Secondly, designing mechanism-based combination therapies will be essential to maximise the benefits of BET inhibition. Lastly, continuing to investigate rare but responsive cancers, such as NUT carcinoma, will provide valuable insights into the long-term potential of these therapies.
While there are still hurdles ahead, the authors of the review 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. This renewed focus on precision medicine and combination therapies offers a promising path forward in the fight against solid tumours, bringing hope to patients and researchers alike.
