Abstract 6768: Targeting the Her2 and ERα receptors has a significant impact on therapy-resistant ER-positive breast cancer

Background: Resistance to endocrine therapy remains a significant clinical hurdle to the management of breast cancer. Mutations in the ESR1 gene (most frequently Y537S) are associated with metastatic disease recurrence in patients previously treated with endocrine therapy. We have shown that silmitasertib, a clinical phase CK2 inhibitor, can inhibit the proliferation of tamoxifen-sensitive and tamoxifen-resistant breast cancer cells in part by disrupting ERα/ERα variant expression. As such, we investigated the antiproliferative and antimigratory efficacy of silmitasertib in CRISPR-edited MCF-7 cells expressing ERαY5237S. Our findings suggest that pharmacological targeting of CK2 may represent an effective strategy in treating ERα-mutated, endocrine therapy-resistant BCa. Methods: Using parental MCF-7 and MCF-7 ERαY537S cells, we assessed cell proliferation in the monolayer cultures, as well as 3D spheroid growth and wound healing activity using live cell imaging in the presence of silmitasertib. We measured the impact of CK2 inhibition on established mitogenic pathways by RT-PCR and/or immunoblot analysis (Her2, Cyclin D1, S6/pS6, S27, ERK/pERK). Subsequently, we assessed the efficacy of combined exposure to the HER2/EGFR inhibitor lapatinib with or without silmitasertib in both MCF-7 and MCF-7 Y537S cells. Results: Our studies show that MCF-7 Y537S cells exhibit enhanced sensitivity to both antiproliferative and anti-migratory effects of silmitasertib compared to parental MCF-7 cells. HER2 was also overexpressed in MCF-7 Y537S, and the combination of lapatinib and silmitasertib, revealed an additive effect on cell proliferation. Conclusion: Our studies suggest that the development of ERαY537S mutations in BCa results in enhanced sensitivity to growth inhibition elicited by CK2 blockade. Our studies provide a convincing rationale for the therapeutic targeting of CK2 in the context of ERα-mutated, endocrine-resistant breast cancer. Citation Format: DeZha Robinson, Hogyoung Kim, Alexandra Caroline Dunn, Clark Jules Perkins, Sihyoung Kim, Sichan kim, Emily Lauren Schenk-Smith, Simak Ali, Matthew Burow, Emma Elkins, Christopher Williams. Targeting the Her2 and ERα receptors has a significant impact on therapy-resistant ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6768.