化疗抗性仍是治疗非小细胞肺癌（NSCLC）患者的主要问题，需要寻求新的概念诱导NSCLC中的细胞毒性。蛋白质毒性是一种通过靶向泛素蛋白酶体系统诱导细胞毒性的有吸引力的创新策略。蛋白酶体抑制剂波替佐米（BTZ）和蛋白毒性压力诱导的艾滋病毒药物奈非那韦（NFV）的联合作用，能够协同诱导蛋白质毒性，并在NSCLC的临床前研究中显示出鼓舞人心的功效。第二代蛋白酶体抑制剂卡菲索米布（CFZ）比BTZ更优，能够在多发性骨髓瘤患者中克服BTZ的抗药性。在这里，我们展示CFZ与NFV相结合，能够优于BTZ + NFV组合，在体外和体内诱导内质网应激和蛋白质毒性，通过在NSCLC中过多积累蛋白质底物蛋白质而实现。有趣的是，NFV通过抑制MDR蛋白质在表达多药抵抗（MDR）蛋白质的NSCLC细胞中的CFZ排泄，增加了CFZ的细胞内可用性。因此，将CFZ与NFV结合可能代表一种未来治疗NSCLC的选择，值得进一步研究。© 2023. 作者。

Chemotherapy resistance is still a major problem in the treatment of patients with non-small-cell-lung carcinoma (NSCLC), and novel concepts for the induction of cytotoxicity in NSCLC are highly warranted. Proteotoxicity, the induction of cytotoxicity by targeting the ubiquitin proteasome system, represents an appealing innovative strategy. The combination of the proteasome inhibitor bortezomib (BTZ) and the proteotoxic stress-inducing HIV drug nelfinavir (NFV) synergistically induces proteotoxicity and shows encouraging preclinical efficacy in NSCLC. The second-generation proteasome inhibitor carfilzomib (CFZ) is superior to BTZ and overcomes BTZ resistance in multiple myeloma patients. Here, we show that CFZ together with NFV is superior to the BTZ + NFV combination in inducing endoplasmic reticulum stress and proteotoxicity through the accumulation of excess proteasomal substrate protein in NSCLC in vitro and ex vivo. Interestingly, NFV increases the intracellular availability of CFZ through inhibition of CFZ export from NSCLC cells that express multidrug resistance (MDR) protein. Combining CFZ with NFV may therefore represent a future treatment option for NSCLC, which warrants further investigation.© 2023. The Author(s).