Proteasome inhibitors (PIs) are currently used in the clinic to treat cancers such as multiple myeloma (MM). However, cancer cells often rapidly develop drug resistance towards PIs due to a compensatory mechanism mediated by nuclear factor erythroid 2 like 1 (NFE2L1) and aspartic protease DNA damage inducible 1 homolog 2 (DDI2). Following DDI2-mediated cleavage, NFE2L1 is able to induce transcription of virtually all proteasome subunit genes. Under normal condition, cleaved NFE2L1 is constantly degraded by proteasome, whereas in the presence of PIs, it accumulates and induces proteasome synthesis which in turn promotes the development of drug resistance towards PIs. Here, we report that Nelfinavir (NFV), an HIV protease inhibitor, can inhibit DDI2 activity directly. Inhibition of DDI2 by NFV effectively blocks NFE2L1 proteolysis and potentiates cytotoxicity of PIs in cancer cells. Recent clinical evidence indicated that NFV can effectively delay the refractory period of MM patients treated with PI-based therapy. Our finding hence provides a specific molecular mechanism for combinatorial therapy using NFV and PIs for treating MM and probably additional cancers.

蛋白酶体抑制剂（PI）目前在临床上用于治疗多发性骨髓瘤（MM）等癌症。然而，由于核因子红细胞 2 样 1 (NFE2L1) 和天冬氨酸蛋白酶 DNA 损伤诱导型 1 同源物 2 (DDI2) 介导的补偿机制，癌细胞通常会迅速对 PI 产生耐药性。在 DDI2 介导的切割之后，NFE2L1 能够诱导几乎所有蛋白酶体亚基基因的转录。在正常情况下，裂解的 NFE2L1 不断被蛋白酶体降解，而在 PIs 存在下，它会积累并诱导蛋白酶体合成，进而促进对 PIs 的耐药性的发展。在这里，我们报告了奈非那韦 (NFV)，一种 HIV 蛋白酶抑制剂，可以直接抑制 DDI2 活性。NFV 对 DDI2 的抑制有效地阻止了 NFE2L1 蛋白水解并增强了癌细胞中 PI 的细胞毒性。最近的临床证据表明，NFV 可以有效延迟 MM 患者接受基于 PI 的治疗的不应期。因此，我们的发现为使用 NFV 和 PI 治疗 MM 和可能的其他癌症的组合疗法提供了特定的分子机制。