Abstract PS3-06-26: Target Proteasome for Immunogenic Synthetic Kill in Triple Negative Breast Cancer

Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype in breast cancer and metastatic TNBC (mTNBC) particularly carries a poor prognosis. While immunotherapy has brought exciting progress in treating mTNBC, only 30∼40% of mTNBC patients with high PD-L1 expression are eligible and treatment resistance is common. Proteasome inhibitors (such as Bortezomib) have been approved by FDA and revolutionized the treatment of multiple myeloma. Proteasome inhibitors can induce immunogenic cell death and anti-tumor immune response in solid tumors, but their application in unselected breast cancer patients has been limited. Previous studies suggest that proteasome addiction may be a therapeutic vulnerabilities in TNBC. Using a computational approach, we analyzed expression of proteasome subunits in TCGA dataset. Our analysis showed that constitutive proteasome subunit PSMB5 was highly expressed in breast cancer tumor tissues but not in adjacent non-tumor tissues. Importantly, a higher level expression of PSMB5 significantly correlated with worse disease free survival in breast cancer patients in TCGA database (p < 0.001). Examination of breast cancer molecular subtypes showed that patients with high PSMB5 expression carry a worse disease free survival than PSMB5 low expression group, particularly in basal like breast cancers. We examined DepMap drug sensitivity database and found that TNBC cell lines are more sensitive to proteasome inhibitors than ER-positive and HER2-positive breast cancers. Basal-like breast cancer (overlapping with TNBC) is significantly more sensitive to proteasome inhibitor Bortezomib than other molecular subtypes. Analysis of transcriptomic data from TCGA and CCLE across different immune subtypes predicts significant greater sensitivity to Bortezomib in fully inflamed (FI) and stroma-restricted (SR) groups than margin-restricted (MR) and immune desert (ID) group. Furthermore, inhibition of proteasome causes synthetic lethality with oncogenic Ras signaling. Our data suggest that targeting protein homeostasis network by proteasome inhibitors such as Bortezomib may represent a novel approach to treating triple negative breast cancers that are already under heightened endoplasmic reticulum stress. Citation Format: X. Zheng, D. Zheng, J. Lu. Target Proteasome for Immunogenic Synthetic Kill in Triple Negative 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 PS3-06-26.