Abstract C130: Identifying a novel therapeutic target, DKK1, in <i>ESR1</i> mutant breast cancers

Abstract Estrogen receptor-positive (ER+) breast cancer accounts for over 75% of all breast cancer diagnoses and remains the most common subtype. While initially responsive to ER-targeted endocrine therapies, about 50% of patients will develop recurrent disease, which is more aggressive and resistant to first-line treatments. Hotspot somatic mutations in ESR1, the gene encoding ER, occur in more than 30% of these recurrences. Y537S ESR1 is among the most prevalent, induces constitutive ER activity, and promotes metastasis through allele-specific chromatin remodeling. Therefore, developing novel and innovative therapeutic strategies to target Y537S ER and its downstream metastatic pathways is critical to mitigating disease. ER is a ligand-dependent master transcriptional regulator. Small molecule ligands can reveal new therapeutic opportunities by engaging neomorphic transcriptional programs. To this end, our lab developed a novel anti-estrogen compound, T6I-29, which effectively blunts tumor growth and metastasis in preclinical models of Y537S ESR1 breast cancer. Transcriptional profiling revealed robust downregulation of DKK1, a secreted glycoprotein known to suppress immune responses in several cancers. However, DKK1 is underexplored in ER+ breast cancers. To assess clinical relevance, we measured circulating DKK1 levels in plasma from 108 ER+ breast cancer patients and 105 healthy donors by ELISA. DKK1 levels were significantly elevated in patients and positively correlated with primary tumor size. DKK1 blockade represents an exciting opportunity to enhance treatment efficacy by stimulating an anti-tumor immune response. The primary target of DKK1 are Natural Killer (NK) cells, an innate immune cell population critical for mitigating tumor cells in circulation. In co-culture assays using Y537S or wild-type ESR1 breast cancer cell lines and primary NK cells from healthy donors, DKK1-high Y537S cells markedly reduced NK cell cytotoxicity, while treatment with T6I-29 restored NK cell function, coinciding with decreased DKK1 expression. Our findings identify DKK1 as a novel immunosuppressive factor in ER+ breast cancer, particularly enriched in Y537S-mutant tumors. DKK1 blockade represents a promising therapeutic strategy to enhance endocrine therapy efficacy in drug-resistant ER+ breast cancers. Citation Format: Kristen Young, Govinda Hancock, Steven Kregel, Grace G. Bushnell, Erik R. Nelson, Donald P. McDonnell, Sean W. Fanning. Identifying a novel therapeutic target, DKK1, in ESR1 mutant breast cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C130.