Abstract Background: ER+ inflammatory breast cancer (IBC) is under-appreciated and under-investigated as an aggressive subset of ER+ breast cancer, despite having rates of metastasis comparable to triple negative (TN) IBC. Recent genome-wide profiling of tumors from patients with metastatic breast cancer has shown that IBC samples have a higher frequency of AURKA amplification than non-IBC samples. Our pilot studies in IBC validate these findings and suggest AURKA is amplified in TNIBC. We hypothesize that Aurora Kinase A (AURKA) is a viable therapeutic target in metastatic IBC and in particular ER+ IBC due synthetic lethality with ARID1A and SMARCA4 in IBC. Methods: We reviewed RNA and DNA data from clinically ordered Boston Gene tumor assays for IBC versus non-IBC breast cancer cases at MDACC. Using ER- IBC cell lines we examined the protein expression of AURKA and tested Alisertib efficacy was tested using the crystal violet staining in IBC cell lines. Senescence was examined using B-gal and ELISA assay. ER+ patient derived organoids were established from ER+PDX as an ER+ IBC model. Results: We previously demonstrated using a large multi-institutional IBC data set including 137 IBC patient tissues analyzed using Affymetrix gene expression arrays, no clear clustering among ER response genes by ER+ subtypes and high AURKA expression in both ER+ and ER- cases. Comparing 21 ER+ IBC to 432 ER+ NON-IBC patient samples, we find AURKA amplified in 14 cases, co-occurrence of AURKA amplification and proposed synthetic lethal targets in 14 cases, and a statistically significant inverse relationship between AURKA and SMARCA4 in IBC. In ER- IBC compared to non-IBC there is no enrichment in AURKA amplification in IBC, but it is highly prevalent occurring in 16 cases out of 28 and with co-occurrence of proposed synthetic lethal gene alterations in 15 cases. Expression of AURKA by immunoblotting in IBC cell lines demonstrates AURKA expression in four IBC cell lines, including two HER2+ (IBC3 and KPL4) and two triple negative (A3250 and SUM149). Higher doses promote reversible senescence assayed by SA-βgal assay and high IL6 by ELISA validated senescence associated secretory phenotype. In collaboration with the PDX program at Baylor College of Medicine led by Dr. Michael Lewis our team has developed a patient derived xenograft (PDX) from an ER+ IBC patient and passaged patient derived organoids for alisertib assessment in a novel ER_ IBC model. Conclusions: AURKA is commonly amplified in IBC and often associated with gene alterations that may predict synthetic lethality to AURKA targeting. In ER+ IBC AURKA amplification is inversely correlated with SMARCA4. We have characterized IBC models with high AURKA expression and demonstrated sensitivity to AURKA inhibition but senescence at higher doses which may provide a direction for targeting resistance or escape. Further studies in ER+ organoids are ongoing. Citation Format: T. Sharma, A. Nasrazadani, W. Ma, J. Chen, M. Kai, B. Lim, M. Lewis, L. Dobrolecki, N. Kotlov, O. Baranov, A. Evdokimova, F. Paradiso, M. Hensley, The MDACC Inflammatory Breast Cancer Team, R. Layman, W. Woodward. Aurora Kinase A (AURKA) a new druggable target in ER+ Inflammatory Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32 (4 Suppl): Abstract nr PS2-09-24.
Sharma et al. (2026) studied this question.