KAT6 Inhibition Shows Path to Overcoming Resistance Mechanisms in ER+ Breast Cancer

KAT6 Inhibition in ER+ Breast Cancer

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Due to its amplification in approximately 12% to 15% of patients with estrogen receptor (ER)–positive breast cancer and ability to repress ER gene transcription, thereby overcoming ESR1-mediated resistance to endocrine therapy, KAT6 had garnered attention as a therapeutic target of interest in the space.1

“KAT6 is a histone [lysine] acetyltransferase complex,” Sarah Naomi Olsen, PhD, an instructor in pediatrics at Boston Children’s Hospital and Dana-Farber Cancer Institute in Massachusetts, said in an interview with OncologyLive. “There is KAT6A as well as its paralog KAT6B. In [patients with] breast cancer, KAT6A is a part of a recurrent chromosomal amplification in chromosome 8. It is amplified in 10% to 15% of patients with ER-positive breast cancer. Due to [this prevalence], there has been a lot of therapeutic develop- ment around targeting KAT6.”

KAT6-Directed Agent Development Is Underway in ER+/HER2– Breast Cancer

The KAT6-targeted agent furthest along in clinical development is PF-07248144. PF-07248144 is a first-in-class, potent, selective inhibitor of KAT6A and KAT6B that has displayed the ability to suppress ER expression in preclinical study.2 The agent also demonstrated potent antitumor activity in ER-positive, HER2-negative patient-derived xenograft models pretreated with palbociclib (Ibrance) and letrozole (Femara).

PF-07248144 was examined as monotherapy in patients with ER-positive, HER2-negative metastatic breast, castration-resistant prostate, or non–small cell lung cancer in part 1A of a phase 1 study (NCT04606446). Data from part 1A led investigators to select 5 mg once daily as the recommended expansion dose of PF-07248144.

Part 1B of the dose escalation portion of the trial enrolled patients with ER-positive, HER2-negative metastatic breast cancer who experienced disease progression following treatment with at least 1 CDK4/6 inhibitor and 1 endocrine therapy.1 Eligible patients also needed to be at least aged 18 years and have an ECOG performance status of 0 or 1 and adequate bone marrow, renal, and liver function.

Patients received PF-07248144 at the recommended expansion dose in combination with 500 mg of fulvestrant (Faslodex). The primary objective was safety and tolerability; secondary objectives included antitumor activity per RECIST 1.1 criteria and assessment of pharmacokinetics.

At the April 30, 2024, data cutoff, with a median follow-up of 16.4 months, updated find- ings presented during the 2024 San Antonio Breast Cancer Symposium showed that efficacy- evaluable patients who received the combination in parts 1B and 2B (n = 43) achieved an objective response rate (ORR) of 37.2% (95% CI, 23.0%- 53.3%). Additionally, the clinical benefit rate was 55.8% (95% CI, 39.9%-70.9%), and the median progression-free survival (PFS) was 10.7 months (95% CI, 5.3-13.8). The median duration of response was not reached (95% CI, 7.2-not evaluable [NE]).

Among patients treated in the second line (n = 23), the ORR was 30.4% (95% CI, 13.2%- 52.9%) and the median PFS was 13.8 months (95% CI, 3.5-NE). These values for patients treated in the third line of therapy (n = 20) were 45.0% (95% CI, 23.1%- 68.5%) and 10.7 months (95% CI, 5.5-13.7), respectively.

The ORR and median PFS for patients with primary endocrine resistance (n = 7) were 57.1% (95% CI, 18.4%-90.1%) and not applicable due to the small sample size, respectively. Among patients with secondary endocrine resistance (n = 36), these values were 33.3% (95% CI, 18.6%-51.0%) and 10.8 months (95% CI, 3.7-16.5), respectively. Patients who received prior fulvestrant (n = 5) achieved an ORR of 60.0% (95% CI, 14.7%-94.7%); PFS data were not reported for these patients. Those without previous fulvestrant use (n = 38) experienced an ORR of 34.2% (95% CI, 19.6%-51.4%) and a median PFS of 7.5 months (95% CI, 3.7-13.8).

Patients who received prior CDK4/6 inhibitor treatment for less than 12 months (n = 10) had an ORR of 40.0% (95% CI, 12.2%-73.8%) and a median PFS of 7.4 months (95% CI, 3.5-NE). Those who received a CDK4/6 inhibitor for more than 12 months (n = 33) experienced an ORR of 36.4% (95% CI, 20.4%-54.9%) and a median PFS of 10.9 months (95% CI, 3.7-16.5).

Notably, antitumor activity was reported with the combination regardless of disease mutational status (Table).1 The highest ORR was reported in patients with PIK3CA/AKT1/PTEN wild-type disease (n = 23) at 43.5% (95% CI, 23.2%-65.5%). The median PFS in this subgroup was 13.7 months (95% CI, 5.6-NE).

In terms of safety in parts 1B and 2B, any-grade treatment-related adverse effects (TRAEs) occurred in all patients; grade 3 or higher TRAEs were reported in 62.8% of patients. The most frequent any-grade TRAEs occurring in at least 20% of patients included dysgeusia (83.7%), neutropenia (65.1%), and anemia (44.2%). No febrile neutropenia or grade 5 TRAEs were reported.

The study authors concluded that their findings suggested treatment with PF-07248144 may be able to overcome endocrine and CDK4/6 inhibitor resistance in patients with ER-positive, HER2-negative metastatic breast cancer. In May 2025, Arvinas announced that a cohort examining PF-07248144 in combination with the investigational, oral proteolysis-targeting chimera ER degrader vepdegestrant (ARV-471) would be added to the phase 1 study.3

“These phase 1 [efficacy] data look quite promising, [however], although some patients responded well, there were no complete responses with [PF-07248144] even when given in [combination] with fulvestrant,” Olsen noted. “Many patients responded much more modestly. These findings prompted [my group] to [examine] if we could identify cooperating vulnerabilities that would enhance the effects of KAT6 inhibition in these patients.”

Enhancing KAT6 Inhibitor Efficacy Via Additional Combination Approaches

During the 2025 American Association for Cancer Research Annual Meeting, Olsen presented findings from a preclinical study she coauthored that sought to identify additional combination partners for KAT6 inhibition for the treatment of patients with ER-positive breast cancer.4 Olsen and her coauthors used CRISPR-based codependency mapping of ER-positive breast cancer cells to identify the transcriptional hub of KAT6A and screen for chromatin-associated proteins that could augment the effects of KAT6 inhibition. The study authors identified MEN1, which encodes for menin, as a potential sensitizer to treatment with KAT6 inhibitors.

“Menin is a well-studied gene in the context of leukemia, but it is much less well studied in the context of solid tumors, including breast cancer,” Olsen said. “Menin inhibitors have shown significant anti-leukemic activity in clinical trials with modest toxicity profiles. Due [to this], we were excited about the potential of combining menin inhibition with KAT6 inhibition [in breast cancer models] to further enhance antitumor activity.”

Data from the preclinical study revealed that KAT6A and menin-KMT2A cooperatively regulate ER-driven genes. Menin and KAT6A also regulated estrogen-induced gene expression and ER chromatin binding; MEN1 loss was shown to sensitize cells to KAT6 inhibition. Additionally, KAT6A, KAT6B, and menin inhibition were found to be cooperative in multiple models of ER-positive breast cancer, including ESR1-mutated patient-derived xenograft models. The study authors concluded that the combination of KAT6 and menin inhibitors could represent a novel approach for the treatment of patients with ER-positive breast cancer and underscored that agents in both classes have displayed manageable toxicity profiles to date.

“Ideally, we want to test this combination approach in clinical trials eventually,” Olsen said. “We are currently working on expanding our preclinical models to include more patient-derived xenograft models and to test this combination more broadly, especially in the ER-resistant [disease] context.”

References

1. Mukohara T, LoRusso PM, Sommerhalder D, et al. PF 07248144 a first in class KAT6 inhibitor in patients with HR HER2 metastatic breast cancer: updated results from phase 1 dose expansion study. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract P4-04-28.
2. Mukohara T, Park YH, Sommerhalder D, et al. A phase 1 dose expansion study of a first-in-class KAT6 inhibitor (PF-07248144) in patients with advanced or metastatic ER+ HER2− breast cancer. J Clin Oncol. 2024;42(suppl 16):3006. doi:10.1200/ JCO.2024.42.16_suppl.3006
3. Arvinas reports first quarter 2025 financial results and provides corporate update. News release. Arvinas. May 1, 2025. Accessed May 8, 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-reports-first-quarter-2025-financial-results-and
4. Olsen SN, Anderson B, Hatton C, et al. Combined inhibition of KAT6 and menin reverses estrogen receptor-driven gene expression programs in breast cancer. Cancer Res. 2025;85(suppl 1):1181. doi:10.1158/1538-7445.AM2025-1181