Abstract 4722: Efficacy of a novel EP300/CBP histone acetyltransferase inhibitor in hormone responsive breast cancer

Mammalian cell identity or cell fate is governed by transcription factors that recruit co-activators to regulate cell-specific gene expression programs. The histone acetyltransferase (HAT) paralogs EP300 and CREB binding protein (CBP) are master transcriptional co-activators that catalyze acetylation of key histones that mark active enhancers, thereby operating at a fundamental step of transcriptional control. Enhancers are often co-opted by cancer cells to control expression of oncogenic transcriptional programs. Identifying cancer-specific dependencies will greatly help prioritize clinical indications that are uniquely vulnerable to HAT inhibition, allowing for precise targeting of cancer cells while sparing normal tissue to maximize the therapeutic window and clinical efficacy. Estrogen receptor (ER) signaling is a validated clinical pathway in over 70% of breast cancer. ER-directed therapies are foundational for the treatment of ER+ breast cancer. However, these therapies are limited by residual ER signaling, which remains online through late-stage disease in a significant fraction of patients. EP300/CBP are critical components of the core ER signaling complex, which is recruited to target DNA by ER and other coactivators, to potentiate ER signaling. Furthermore, CBP and EP300 are dependency factors in the context of ESR1 mutations that arise in metastatic disease to facilitate disease progression. We report for the first time the activity of a novel, potent, selective and in vivo active EP300/CBP HAT inhibitor for the treatment of ER-positive (ER+) breast cancer. CPI-1 has pM biochemical and nM activity in ER+ breast cancer cell lines. Analysis of nascent and steady-state RNA levels facilitated by PRO-seq and RNA-seq technologies revealed a time and dose-dependent suppression of the ER transcriptome. Dynamic gene regulation was coupled with enhancer RNA (eRNA) transcription and enhancer acetylation, to identify enhancers that were hypersensitive to CBP/EP300 HAT inhibition. CPI-1 demonstrates significant tumor growth inhibition in a xenograft mouse model of ER+ breast cancer as a monotherapy and together with an ER targeting agent, the combination displays superior efficacy to either treatment alone. These results highlight the potential of targeting key oncogenic transcriptional nodes with complementary therapeutic mechanisms to achieve superior results and reveals the potential utility of inhibiting the HAT domain of EP300/CBP in molecularly refined