Targeting AR-Positive Breast Cancer with FT-6876: A Novel CBP/p300 Bromodomain Inhibitor

Triple negative breast cancer (TNBC) is a significant medical challenge, often addressed with chemotherapy. Recent developments have seen the approval of PARP inhibitors and an immune checkpoint inhibitor for certain TNBC patients. The androgen receptor (AR) is present in 20-30% of TNBC cases and can promote tumor growth and survival by activating transcription of genes typically regulated by the estrogen receptor (ER). This process requires key co-factors, including the structurally similar CBP and p300 proteins, which have bromodomain and lysine acetyl transferase activity.

A new compound, FT-6876, has been identified as a potent and selective inhibitor of the bromodomain in CBP/p300. The hypothesis is that FT-6876 will affect chromatin structure and reduce AR's transcriptional activity at specific gene loci, leading to a decrease in tumor growth. This was supported by an observed reduction in the histone mark H3K27Ac in AR+ breast cancer cells treated with FT-6876, which returned to baseline levels upon compound withdrawal, indicating a reversible effect.

Further analysis using precision run-on sequencing (PRO seq) revealed that FT-6876 significantly influenced the transcriptional activity of AR and ER pathways. ChIPseq confirmed that the reduction in H3K27Ac at certain promoters was associated with decreased CBP/p300 binding and reduced transcription. The compound showed a time-dependent anti-proliferative effect, with optimal inhibition observed after 10 days of exposure, and this effect persisted even after drug withdrawal.

A correlation was found between the compound's growth-inhibitory effects and the level of AR expression in breast cancer cell lines. In animal models, FT-6876 induced tumor stasis at doses that were well tolerated, accompanied by a decrease in H3K27Ac, modulation of AR and ER target genes, and a reduction in Ki67, a marker of cell proliferation.

The study concludes that FT-6876 is a promising CBP/p300 bromodomain inhibitor with demonstrated efficacy in preclinical models of AR+ breast cancer. The findings were presented by Maureen Caligiuri and colleagues at the Annual Meeting of the American Association for Cancer Research in 2020.