New generation approaches revive BET protein inhibitors in solid tumors

BET proteins, especially BRD4, drive oncogenic transcription in solid tumors. First‑generation inhibitors (JQ1, molibresib, birabresib) showed preclinical promise but failed clinically due to modest efficacy, dose‑limiting thrombocytopenia, and resistance (isoform switching, compensatory PI3K/AKT/WNT signaling). Responses are best in NUT carcinoma and castration‑resistant prostate cancer. Next‑generation approaches-BD2‑selective inhibitors, PROTAC degraders, and rational combinations with PARP inhibitors, AR antagonists, or immune checkpoint blockade-offer renewed hope. This review summarises the current landscape and future directions for BET targeting in solid oncology.

Introduction

BET proteins (BRD2, BRD3, BRD4, BRDT) bind acetylated chromatin via two bromodomains (BD1 and BD2). BRD4 recruits P‑TEFb to phosphorylate RNA polymerase II, driving expression of oncogenes like MYC. In solid tumors, BRD4 is particularly critical at super‑enhancers. Unlike hematological cancers, solid tumors have complex transcriptional networks, making BET inhibition alone less effective.

First‑generation BET inhibitors

Compounds such as JQ1, molibresib, and birabresib effectively displaced BRD4 and reduced MYC in preclinical models. In clinical trials, they produced modest responses, especially in NUT carcinoma (where BRD4 fusions are driver events) and some prostate cancers. However, short half‑lives, thrombocytopenia (dose‑limiting), and acquired resistance-via BRD4 isoform switching (long vs. short) and activation of bypass pathways-limited their utility.

Next‑generation inhibitor design

BD2‑selective inhibitors (e.g., ABBV‑744) target BD2 while sparing BD1, reducing thrombocytopenia while maintaining anti‑tumor activity. PROTACs (e.g., ARV‑771, MZ1) degrade BET proteins completely, overcoming isoform switching and offering deeper suppression. Bivalent inhibitors (e.g., AZD5153) engage both bromodomains for higher affinity. Other emerging approaches include dual BET/kinase or BET/HDAC inhibitors and agents that disrupt BRD4‑driven phase separation at super‑enhancers.

Combination strategies

Combinations are essential. BETi + PARP inhibitors exploit BETi‑induced DNA repair defects, showing synergy in TNBC and ovarian cancer. BETi + AR antagonists improve outcomes in castration‑resistant prostate cancer. BETi + immune checkpoint blockade shows preclinical promise, though toxicity can be an issue. BETi + HDAC or CDK inhibitors are also being explored.

Clinical trial experience

Trials with molibresib and birabresib confirmed target engagement and activity in NUT carcinoma, but intermittent dosing was needed to manage thrombocytopenia. Combinations like ZEN‑3694 + enzalutamide or talazoparib have shown early signals of efficacy. However, many trials were terminated due to low single‑agent activity, toxicity, or pharmacokinetic challenges.

Future directions

Key priorities include: developing more selective/degradative agents; identifying predictive biomarkers (e.g., MYC amplification, BRD4 dependency) to guide patient selection; designing rational, mechanism‑based combinations; optimising dosing schedules to reduce haematological toxicity; and continuing to study rare responsive tumors like NUT carcinoma to define clinical utility.

Conclusions

BET inhibition in solid tumors is a promising but still‑optimising field. First‑generation agents validated the concept but faced major hurdles. Next‑generation modalities and strategic combinations hold real potential. Success will require biomarker‑driven trials, careful toxicity management, and a deeper understanding of resistance mechanisms.