化疗耐药是三阴性乳腺癌（TNBC）患者治疗中的一个主要问题。临床前数据表明，TNBC 依赖于蛋白酶体；然而，临床观察表明，蛋白酶体抑制剂在 TNBC 中的疗效可能有限，这表明需要联合治疗。我们在 TNBC 细胞系和原代细胞中比较了硼替佐米和卡非佐米及其与奈非那韦和洛匹那韦的组合的细胞毒活性，功能性蛋白酶体抑制，以及诱导未折叠蛋白反应 (UPR)。此外，我们评估了 sXBP1、ABCB1 和 ABCG2 在药物组合的细胞毒性活性中的参与情况。卡非佐米通过蛋白酶体 β5   β2 抑制，在 TNBC 中的细胞毒性比硼替佐米更强，硼替佐米抑制 β5   β1 蛋白酶体亚基。奈非那韦或洛匹那韦显着增强卡非佐米的细胞毒性。卡非佐米与洛匹那韦在体外通过 TNBC 中过量蛋白酶体底物蛋白的积累诱导内质网应激和促凋亡 UPR。此外，洛匹那韦通过抑制卡非佐米从表达高水平和活性ABCB1（但不表达ABCG2）的细胞中输出来增加卡非佐米的细胞内利用度。卡非佐米联合奈非那韦/洛匹那韦的蛋白酶体抑制代表了TNBC的潜在治疗选择，值得进一步研究。© 2024。作者。

Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies.We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations.Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2.Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.© 2024. The Author(s).