Pharmacologic Inhibition of KAT6A/B Induces Senescence and Impairs Tumor Growth in Preclinical Cancer Models

Abstract

Epigenetic regulation is a fundamental mechanism controlling gene expression, and its dysregulation is widely implicated in cancer. Among key epigenetic regulators, lysine acetyltransferases KAT6A and KAT6B (also named MYST3 and MYST4, respectively) have gained increasing attention due to their roles in chromatin remodeling, gene activation, and cell proliferation. Chemical biology breakthroughs have now enabled the design of selective pharmacologic inhibitors of the KAT6A/B acetyltransferase domains. It has been demonstrated in preclinical models that inhibition of KAT6A/B induces a state of cellular senescence—a irreversible cell-cycle arrest—thereby preventing tumor growth in various cancer models. This paper covers the biology of KAT6A/B, how their inhibition induces senescence, and the therapeutic potential for these findings in cancer treatment.

Introduction: The Epigenetic Landscape of Cancer

Cancer arises from the accumulation of genetic and epigenetic alterations that destabilize normal cellular homeostasis. While much attention has been placed on mutations in oncogenes and tumor suppressor genes, epigenetic disruption—such as aberrant DNA methylation, histone modification, and chromatin remodeling—is now recognized as a basic hallmark of malignancy.

Histone acetylation, a highly characterized epigenetic modification, affects chromatin structure and gene transcription. It is regulated by two families of enzymes with counteracting activities: histone acetyltransferases (HATs), which add acetyl groups to histone lysine residues, and histone deacetylases (HDACs), which remove them. In the HAT family, KAT6A and KAT6B were found to be key regulators of gene expression programs associated with cell growth, differentiation, and development^[1]^.

In many cancers, KAT6A and KAT6B are overexpressed or genomically altered, driving tumorigenesis. However, these enzymes were previously pharmacologically inaccessible. The identification of selective KAT6A/B inhibitors has opened up new avenues in the therapeutic targeting of cancer, particularly by taking advantage of the natural cellular process of senescence to inhibit the growth of tumor cells^[2]^.

KAT6A and KAT6B: Structure, Function, and Role in Cancer

KAT6A and KAT6B are members of the MYST family of HATs, which are characterized by the presence of a conserved MYST domain that has an acetyl-CoA binding pocket and a zinc finger. They acetylate histone H3 on lysine 9 (H3K9ac) and lysine 14 (H3K14ac), which modifications are associated with transcriptional activation^[3]^.

In addition to their catalytic role, KAT6A/B function within multiprotein complexes that regulate chromatin structure and gene transcription. They interact with co-factors such as BRPF1 and ING5 that direct them to specific genomic locations. Via these interactions, KAT6A/B influence gene programs that regulate cell cycle progression, stem cell maintenance, and lineage commitment.

KAT6A is often amplified or rearranged in acute myeloid leukemia (AML) and medulloblastoma, while mutations of KAT6B are found in a variety of solid tumors, including breast and colorectal cancer. Their overexpression is associated with poor prognosis and treatment resistance, making them attractive targets for therapy^[4]^.

Pharmacologic Inhibition of KAT6A/B: A New Therapeutic Strategy

The identification of small-molecule inhibitors that selectively inhibit the catalytic domains of KAT6A/B is a breakthrough in epigenetic therapy. WM-1119, among others, competively occupies the acetyl-CoA binding pocket of KAT6A and KAT6B and inhibits their histone acetyltransferase activity.

Unlike conventional cytotoxic agents that eliminate actively proliferating cells, WM-1119 does not induce apoptosis. Rather, it triggers a profound state of cellular senescence characterized by the presence of irreversible cell cycle arrest, flattening of the cell morphology, increased β-galactosidase activity, and induction of p21—a cyclin-dependent kinase inhibitor^[5]^.

The non-lethal mechanism of action is also important in avoiding collateral damage to healthy tissue. Furthermore, senescent tumor cells can trigger immune clearance via the senescence-associated secretory phenotype (SASP), which promotes immune surveillance.

Figure 1: Targeting KAT6A/B as a New Therapeutic Strategy for Cancer Therapy^[6]^

Cellular Senescence: A Barrier Against Tumorigenesis

Senescence is a complex and multiform biological program that functions as a natural brake on uncontrolled cellular growth. It can be triggered by a variety of stimuli, including DNA damage, oncogene activation, oxidative stress, and, more recently, epigenetic regulation.

As a response to KAT6A/B inhibition, chromatin is remodeled extensively, leading to the repression of cell cycle-driving genes—particularly E2F and Myc-controlled ones. The induction of tumor suppressors p21 and p16 thereafter solidifies the senescent phenotype^[7]^.

Interestingly, this is done without any DNA damage, which means that epigenetic reprogramming alone is enough to induce senescence. This offers a better therapeutic window because DNA-damaging agents have genomic instability effects in the long run.

The KAT6A/B inhibitor-induced senescence is irreversible and stable, i.e., the tumor cells fail to re-enter the cell cycle even when the drug is withdrawn. This stability makes the strategy highly appealing for long-term suppression of tumors^[8]^.

Preclinical Evidence in Hematologic and Solid Tumors

In vitro studies on leukemia, lymphoma, and solid tumor (e.g., breast, lung, colorectal) cancer cell lines have all demonstrated the promise of KAT6A/B inhibitors in halting proliferation and inducing senescence. The actions are dose-dependent and occur within days of exposure.

Systemic administration of WM-1119 in animal models suppresses tumor growth significantly. Mice with AML and medulloblastoma xenografts treated with WM-1119 have smaller tumor sizes, longer survival, and higher markers of senescence in the tumor tissues.

Importantly, the inhibitor is also well-tolerated in vivo with very minimal hematologic toxicity and no weight loss or organotoxicity. This favorable safety profile suggests a therapeutic index that can be developed clinically.

Such universality of effects across tumor types implies broad potential for KAT6A/B inhibition in oncology, with particular utility for those cancers lacking targetable genetic mutations^[9]^.

Insights into Mechanism from Genomic and Epigenomic Studies

Genome-wide transcriptomic studies have yielded insight into the molecular changes induced by KAT6A/B inhibition. RNA sequencing reveals suppression of DNA replication, mitotic spindle assembly, and metabolic processes driving rapid proliferation.

Chromatin immunoprecipitation (ChIP) assays show that WM-1119 decreases H3K9ac and H3K14ac on promoters of cell cycle genes, validating direct epigenetic control. At the same time, there is a rise in repressive histone modifications like H3K27me3, which consolidate transcriptional silencing.

These changes converge on a transcriptional program reminiscent of natural senescence, including activation of the p53 pathway and inhibition of Myc targets. Together, these observations support a model whereby KAT6A/B maintain gene expression programs supporting proliferation that are dismantled upon inhibition^[10]^^.^

Furthermore, integrated proteomic analyses indicate reduced expression of chromatin remodelers and DNA repair proteins, further incapacitating the tumor's capacity for recovery and adaptation.

Senescence-Associated Secretory Phenotype (SASP): A Double-Edged Sword

While senescent cells are growth-arrested, they are metabolically active and secrete a variety of cytokines, chemokines, and growth factors collectively referred to as the SASP. This phenotype has beneficial and detrimental effects.

Firstly, the SASP facilitates recruitment of macrophages, natural killer cells, and T lymphocytes, which recognize and eliminate senescent tumor cells. This immunogenic clearance is critical for durable responses to therapy.

Alternatively, chronic SASP activity can promote inflammation, tissue remodeling, and in some contexts, tumor development. Accordingly, the combination of KAT6A/B inhibitors with medications that modulate the immune microenvironment—e.g., immune checkpoint inhibitors or senolytics—may optimize therapeutic response^[11]^.

Defining and managing the SASP response will be paramount in KAT6A/B inhibition translation into effective clinical models.

Implications for Drug Resistance and Tumor Relapse

Resistance to treatment is one of the biggest hurdles in oncology. In contrast to targeted treatments that are liable to resistance through mutations in the target protein, epigenetic treatments have more far-reaching effects and are less likely for single-point failure.

KAT6A/B inhibitors constitute a non-mutational strategy to undermine tumor fitness, which is suitable for those tumors with high heterogeneity or without a prevalent oncogenic driver. Additionally, the induction of senescence rather than forceful cell death can reduce selective pressure for clones resistant to it.

Yet, some tumor cells are able to escape senescence by activating alternative survival pathways or epithelial-to-mesenchymal transition (EMT). Combination therapies with these escape routes may further enhance the efficacy of KAT6A/B inhibition.

Long-term studies using preclinical models will be required to compare relapse rates and identify resistance biomarkers^[12]^.

KAT6A/B Inhibition Combined with Existing Therapies

Because of its unique mechanism, KAT6A/B inhibition is well-suited for combination therapy. WM-1119 combined with DNA-damaging agents or CDK4/6 inhibitors results in synergistic tumor suppressive activity in preclinical models.

Furthermore, epigenetic priming with KAT6A/B inhibition may be able to sensitize tumors to immune checkpoint blockade by enhancing antigen presentation and reversing immune evasion. Experiments to test this hypothesis are being planned.

The synergistic or additive nature of these combinations supports the potential of KAT6A/B inhibitors to augment standard-of-care regimens and improve response rates, especially in refractory cancers.

Pharmacokinetic profiling indicates that inhibitors have suitable oral bioavailability and distribution, making them highly amenable to combination approaches in the absence of dosing interference.

Figure 2: Overview of strategies to target ER signaling^[13]^

Toxicity, Tolerability, and Future Clinical Trials

Preclinical toxicity testing in mice and non-human primates has exhibited a promising safety profile for KAT6A/B inhibitors with no significant effects on the bone marrow, liver, or gastrointestinal tract. Unlike pan-HDAC inhibitors, which are associated with fatigue, cytopenias, and cardiac issues, KAT6A/B inhibition has been more selective and well-tolerated.

This safety profile will be critical in advancing into human trials, particularly in early-stage patients or combination therapies. Biomarkers of H3K9ac loss and p21 induction can serve as pharmacodynamic readouts to determine response.

First-in-human phase I trials will probably target hematologic malignancies and solid tumors with high KAT6A/B expression. Patient stratification based on molecular profiling will be required to realize maximal therapeutic benefit.

The outcomes of such trials will determine the clinical promise of this novel epigenetic strategy and possibly usher in a new era of cancer therapy^[14]^.

Conclusion

Pharmacologic inhibition of KAT6A and KAT6B represents a paradigm shift in cancer therapy, targeting the epigenetic machinery of malignant growth. By inducing stable, non-lethal senescence, KAT6A/B inhibitors effectively inhibit tumor growth while preserving tissue integrity.

Preclinical trials have demonstrated robust antitumor activity in a variety of models, with compelling mechanistic rationale and minimal toxicity. The senescence-based approach offers unique advantages regarding durability, immunogenicity, and evading resistance.

With these inhibitors progressing to clinical trial, they hold the promise of broad applicability, especially in tumors with limited existing targeted therapies. Current efforts will maximize their use, establish optimal combinations, and develop biomarkers to guide personalized therapy.

In the new field of epigenetic oncology, inhibition of KAT6A/B is a promising way to reshape the future of cancer therapy.

references

[1] Fu, J.-Y., Huang, S.-J., Wang, B.-L., et al. (2024). Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity. Cell Metabolism, 36(1), 1–15.

[2] Voss, A. K., & Thomas, T. (2019). The key roles of the lysine acetyltransferases KAT6A and KAT6B in development and disease. Cellular and Molecular Life Sciences, 76(4), 673–693.

[3] Zhang, L., Wang, H., & Liu, Y. (2023). BRPF1-KAT6A/KAT6B complex: molecular structure, biological function, and human disease. Epigenetics & Chromatin, 16(1), 1–14.

[4] Henlius Biotech, Inc. (2025). Identification of novel KAT6A/B inhibitors with enhanced antitumor activity and reduced hematologic toxicity. AACR Annual Meeting Abstracts, Abstract 6976.

[5] Baell, J. B., Leaver, D. J., Hermans, S. J., et al. (2018). Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature, 560(7717), 253–257.

[6] Zheng, T., Wang, S., Liu, W., & Lu, Y. (2025). Targeting KAT6A/B as a New Therapeutic Strategy for Cancer Therapy. Journal of Medicinal Chemistry.

[7] La Porta, C. A. M., Zapperi, S., & Sethna, J. P. (2013). Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells. arXiv preprint arXiv:1308.6028.

[8] Sharma, S., Stupple, P. A., Monahan, B. J., et al. (2023). Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer. Cell Chemical Biology, 30(10), 1191–1210.

[9] Mukohara, T., Park, Y. H., Sommerhalder, D., et al. (2024). Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial. Nature Medicine, 30(8), 2242–2250.

[10] Lee, H., Kim, S., & Park, J. (2022). KAT6A mutations in Arboleda-Tham syndrome drive epigenetic dysregulation. Human Genetics, 141(4), 567–578.

[11] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013). Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. The Journal of Clinical Investigation, 123(3), 966–972.

[12] Jeselsohn, R., & Polyak, K. (2023). HATS off to KAT6A/B inhibitors: A new way to target estrogen-receptor-positive breast cancer. Cell Chemical Biology, 30(10), 1101–1103.

[13] Herrera-Abreu, M. T. , Palafox, M. , Asghar, U. , Rivas, M. A. , Cutts, R. J. , & Garcia-Murillas, I. , et al. (2016). Early adaptation and acquired resistance to cdk4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Research, 2301.

[14] Lindeman, L., MacPherson, S., Nuttall, S., et al. (2021). First-in-class KAT6A/KAT6B inhibitor CTx-648 (PF-9363) demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation. Cancer Research, 81(13_Supplement), Abstract 1130.