Dual Aptamers-Based SETDB1 PROTACs as Effective Anti-Tumor Strategies for Breast Cancer

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• PROteolysis TArgeting Chimeras (PROTACs) represent a novel therapeutic strategy for targeting oncogenic proteins.
• SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a crucial epigenetic regulator involved in breast cancer progression, drug resistance, and immune evasion.

Purpose of the Study:

• To develop and characterize dual aptamer-based PROTACs targeting SETDB1 for breast cancer therapy.
• To evaluate the efficacy of these PROTACs in inhibiting breast cancer cell proliferation, migration, and drug resistance, and in modulating the tumor immune microenvironment.

Main Methods:

• Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was used to identify a high-affinity ssDNA aptamer against SETDB1.
• The SETDB1 aptamer was conjugated with the AS1411 aptamer to create single-strand (AP-SETDB1-S6A) and partial double-strand (AP-SETDB1-D2) PROTACs.
• PROTAC activity was assessed through cell proliferation, migration, drug sensitization, T cell cytotoxicity, and in vivo tumor growth assays.

Main Results:

• Both AP-SETDB1-S6A and AP-SETDB1-D2 demonstrated good serum stability and effectively induced proteasome-dependent degradation of SETDB1 in breast cancer cells by recruiting MDM2.
• These PROTACs significantly inhibited breast cancer cell proliferation and migration, and resensitized tamoxifen-resistant cells.
• The PROTACs enhanced CD8+ T cell-mediated cytotoxicity against breast cancer cells and suppressed tumor growth in vivo.

Conclusions:

• Dual aptamer-based PROTACs targeting SETDB1 offer a promising therapeutic approach for breast cancer.
• These novel agents demonstrate potent anti-cancer activity, including overcoming drug resistance and modulating the immune response, highlighting their potential for clinical translation.