Palazestrant（一种CERAN）与OP-3136（一种KAT6抑制剂）联用可协同下调细胞增殖及转移相关基因特征

Histone lysine acetyltransferases KAT6A and KAT6B are epigenetic enzymes involved in regulating transcription of oncogenic genes, including ERalpha, 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-alpha 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-alpha/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.