Abstract 2949: Palazestrant, a CERAN, in combination with OP-3136, a KAT6 inhibitor, synergistically downregulates cell proliferation and metastasis related gene signatures.

Abstract Histone lysine acetyltransferases KAT6A and KAT6B are epigenetic enzymes involved in regulating transcription of oncogenic genes, including ERα, MYC, and cell cycle drivers. We previously reported that OP-3136, a KAT6 inhibitor, shows enhanced efficacy in vitro and in vivo in ER+/HER2– breast cancer models when combined with the complete estrogen receptor antagonist (CERAN) palazestrant (OP-1250) (Palanisamy et al., 2024). Here, we further investigate the mechanisms of this synergy by characterizing treatment-dependent transcriptional changes.We used T47D, an ER+/HER2– ESR1–wild-type breast cancer cell line overexpressing KAT6A, as an in vivo xenograft model. We evaluated the impact of OP-3136, palazestrant, and the combination in comparison to monotherapy and OP-3136 combination with the approved antiestrogen, fulvestrant. Xenografts were treated for 28 days, and bulk RNA sequencing was performed on isolated tumors.Palazestrant and OP-3136 combination resulted in greater suppression of genes associated with cell proliferation and cell-cycle progression (Hallmark E2F and G2M gene sets) than monotherapy treatment. While the fulvestrant–OP-3136 combination also reduced these gene sets, the palazestrant combination caused stronger downregulation, consistent with observed efficacy responses. The palazestrant-OP-3136 combination also showed the most potent suppression of key transcriptional regulators of ER+ breast cancer, including PGR, E2F1, MYC, GATA3, and FOXA1.Palazestrant plus OP-3136 further suppressed expression of MTORC1 and TNF-α via NFκB signaling pathways. These pathways were also downregulated by the fulvestrant–OP-3136 combination but to a lesser extent. The observed effects exceeded expected additive responses, indicating that CERAN plus KAT6 inhibition synergistically regulate these pathways at the transcriptional level. Because inhibition of the PI3K/mTOR/AKT axis mitigates endocrine resistance and TNF-α/NFκB signaling promotes metastasis and invasion, these findings suggest that combining a KAT6 inhibitor with palazestrant may represent a promising strategy to overcome resistance in metastatic ER+ breast cancer.Collectively, these data demonstrate that palazestrant and OP-3136 synergize to suppress genes associated with proliferation, survival, and metastasis. The transcriptional changes align with enhanced anti-tumor efficacy and establish a mechanistic rationale for this combination over fulvestrant in ER+ breast cancer. The palazestrant–OP-3136 combination is currently being evaluated in a phase I clinical trial in ER+/HER2– metastatic breast cancer patients. Citation Format: Susanna A. Barratt, Gopinath S. Palanisamy, Azita Ghodssi, Chelsea Hope, Guadelupe Peña, Srinivasan Jayaraman, Raymond A. Ng, David C. Myles. Palazestrant, a CERAN, in combination with OP-3136, a KAT6 inhibitor, synergistically downregulates cell proliferation and metastasis related gene signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2949.