Abstract PS4-03: Calcium Channel Blockers Enhance Efficacy of TROP2-ADC in Overcoming Resistance in Advanced Triple-Negative Breast Cancer

Abstract The TROP2-directed antibody-drug conjugate (TROP2-ADC) has been approved for treating advanced triple-negative breast cancer (TNBC) that has progressed after chemotherapy. Recent findings from the ASCENT trial indicated that sacituzumab govitecan (SG), compared with standard chemotherapy, significantly prolongs median progression-free survival and overall survival in patients with advanced or refractory TNBC, reducing the risk of disease progression by 59% and the risk of death by 52%. However, approximately 20% of patients exhibit primary resistance to SG, experiencing disease progression within 3 months. Therefore, exploring the molecular mechanisms underlying TROP2-ADC resistance is crucial for reversing drug resistance and improving the prognosis of patients with advanced TNBC. In this study, we retrospectively observed that advanced TNBC patients with hypertension who were co-treated with SG and nifedipine displayed better survival times compared to advanced TNBC patients without hypertension who were treated with SG alone. Based on these findings, we constructed TNBC patient-derived xenografts (PDXs) that were either sensitive or insensitive to TROP2-ADC. We found that combining calcium channel blockers (CCBs) with TROP2-ADC significantly improved anti-tumor efficacy and maintained a manageable safety profile in TROP2-ADC insensitive models, both in vivo and in vitro. High-throughput sequencing of TNBC patients treated with TROP2-ADC revealed that pathways related to vesicle trafficking, calcium ion binding, and cell membrane processes were highly enriched in resistant patients. Mechanistically, excess intracellular calcium activated PKC and PACSIN2, leading to increased caveolae-mediated endocytosis. This resulted in defective plasma membrane localization of TROP2, contributing to TROP2-ADC resistance. In conclusion, our results provide insight into the potential mechanisms of TROP2-ADC resistance and suggest that combining CCBs with TROP2-ADC may offer a new therapeutic strategy for patients resistant to TROP2-ADC. Citation Format: Jieer Luo, Qun Lin, Yu Shi, Zhuxi Duan, Jinpeng Luo, Xiaolin Fang, Chang Gong. Calcium Channel Blockers Enhance Efficacy of TROP2-ADC in Overcoming Resistance in Advanced Triple-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS4-03.