Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, 9000, St. Gallen, Switzerland.
Cantonal Hospital St. Gallen, Rorschacherstrasse 95 Haus 09/218, 9007, St. Gallen, Switzerland.
Sci Rep. 2023 Mar 17;13(1):4411. doi: 10.1038/s41598-023-31400-6.
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.
化疗耐药仍然是非小细胞肺癌（NSCLC）治疗中的一个主要问题，因此非常有必要提出诱导 NSCLC 细胞毒性的新概念。蛋白毒性，即通过靶向泛素蛋白酶体系统诱导细胞毒性，代表了一种有吸引力的创新策略。蛋白酶体抑制剂硼替佐米（BTZ）和蛋白毒性应激诱导的 HIV 药物奈非那韦（NFV）的联合使用可协同诱导蛋白毒性，并在 NSCLC 的临床前研究中显示出令人鼓舞的疗效。第二代蛋白酶体抑制剂卡非佐米（CFZ）优于 BTZ，并克服了多发性骨髓瘤患者对 BTZ 的耐药性。在这里，我们证明 CFZ 联合 NFV 通过在体外和离体 NSCLC 中积累过多的蛋白酶体底物蛋白，在诱导内质网应激和蛋白毒性方面优于 BTZ+NFV 联合用药。有趣的是，NFV 通过抑制表达多药耐药（MDR）蛋白的 NSCLC 细胞中 CFZ 的外排来增加 CFZ 的细胞内可用性。因此，CFZ 联合 NFV 可能成为 NSCLC 的一种未来治疗选择，值得进一步研究。
