Dual Inhibition of KAT6A/B and Menin: A Promising Strategy for ER+ Breast Cancer

Resistance to endocrine therapy remains a formidable barrier in the management of estrogen receptor–positive (ER+) breast cancer. Although selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER degraders (SERDs) can initially control tumor growth, resistance inevitably develops—often while ER signaling persists.¹ This underscores the urgent need for novel therapeutic strategies that disrupt ER‑driven transcriptional programs by targeting chromatin regulators.

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The MYST family histone acetyltransferases KAT6A and its paralog KAT6B play a critical role in mediating ER‑driven gene expression. KAT6A is amplified or overexpressed in roughly 10% to 15% of ER+ breast cancers, where its activity correlates with aggressive tumor behavior and poor prognosis.² A breakthrough inhibitor, PF‑9363 (also CTx-648; Pfizer), has been developed as a potent, selective, and orally bioavailable compound targeting KAT6A/B. In preclinical models, PF‑9363 was shown to suppress H3K23 acetylation and reduce RNA polymerase II binding at estrogen-signaling genes, leading to significant tumor inhibition—even in endocrine-resistant settings.

Using an epigenetic-focused CRISPR‑Cas9 screen, Menin (encoded by MEN1) was identified as a key codependency in ER+ breast cancer cells treated with PF‑9363. Knockout of MEN1 significantly enhanced sensitivity to KAT6A/B inhibition. Menin, a chromatin adaptor protein often associated with KMT2A/MLL1 complexes, is highly expressed in more than half of breast cancers and strongly associated with ER+ subtypes.

Synergistic Effects Through Dual Inhibition

Co‑treatment with KAT6A/B and menin inhibitors—namely PF‑9363 and SNDX‑5613 (revumenib, Revuforj; Syndax Pharmaceuticals)—produces marked synergistic anti‑proliferative effects in ER+ cell lines, but not in ER– models.² Mechanistically, the combination disrupts ER‑driven transcription through two pivotal actions. First, it reduces ESR1 (ERα) gene and protein expression. Second, it displaces both KAT6A and Menin–KMT2A from the promoters of ER target genes, leading to loss of RNA polymerase II binding and chromatin accessibility in those regions.^2,3 These effects are more robust than those produced by either inhibitor alone.

Efficacy in 3D Organoids and Patient-Derived Xenografts

The synergy extends beyond cell lines. In 3D patient‑derived organoid (PDxO) models of ER+ breast cancer, including both ductal and lobular carcinoma variants, the combined inhibition displayed enhanced suppression of ER-driven gene expression and organoid growth. Moreover, in patient‑derived xenograft (PDX) models, including those with endocrine-resistant and ESR1-mutated tumors, the dual therapy maintained its efficacy in vivo, highlighting its potential relevance to advanced, treatment‑refractory disease.²

Both PF‑9363 and SNDX‑5613 are advancing in clinical development. PF‑9363 and other KAT6A/B inhibitors like PF‑07248144 (Pfizer) are undergoing early‑phase trials, with PF‑07248144 already demonstrating a 37% objective response rate and manageable toxicity in heavily pretreated metastatic ER+ breast cancer patients. SNDX‑5613, a menin inhibitor, has received FDA approval for KMT2A‑rearranged leukemia, suggesting a favorable safety profile.² These developments provide strong ground for considering clinical evaluation of the KAT6A/B plus Menin inhibitor combination in ER+ breast cancer.³

Conclusion

The dual inhibition of KAT6A/B and Menin represents a novel epigenetic intervention capable of overriding both endocrine sensitivity and resistance in ER+ breast cancer. By targeting two critical chromatin complexes that jointly sustain ER‑driven transcription, this combination achieves superior suppression of tumor growth and gene expression. With both inhibitor classes already in clinical trials and demonstrating tolerability, this strategy offers a compelling new avenue for personalized therapy, particularly in patients with refractory disease. Future research should assess combination regimens across diverse genomic backgrounds and explore optimal dosing and safety in clinical settings.¹

REFERENCES

1. KAT6A/B and Menin Inhibition Synergize to Suppress ER+ Breast Cancer | Docwire News. Docwire News. Published 2025. Accessed September 3, 2025. https://www.docwirenews.com/post/kat6a-b-and-menin-inhibition-synergize-to-suppress-er-breast-cancer

2. Olsen SN, Anderson B, Hatton C, et al. Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer. Cell Rep Med. 2025;6(7):102192. doi:10.1016/j.xcrm.2025.102192

3. Sharma S, Chung CY, Uryu S, et al. Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer. Cell Chem Biol. 2023;30(10):1191-1210.e20. doi:10.1016/j.chembiol.2023.07.005