奥司他替尼是一种有前景的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），用于治疗携带EGFR激活突变的肺腺癌（LUAD）患者，然而几乎所有患者最终都会对奥司他替尼产生耐药性，从而限制了其长期疗效。细胞自噬是一种重要的细胞再循环过程，促进了对奥司他替尼的耐药性。准确和高效地识别自噬调控因子对于减轻奥司他替尼耐药性具有重要意义。本研究发现，Cezanne是卵巢肿瘤蛋白酶（OTU）去泛素化家族的成员，是一种自噬调节因子。Cezanne在奥司他替尼耐药细胞中高表达，并且Cezanne的过表达促进了奥司他替尼耐药性，而自噬抑制剂氯喹（CQ）则逆转了这个过程。在Cezanne过表达细胞中，即使在没有自噬诱导剂雷帕霉素和Earle's平衡盐溶液（EBSS）的情况下，自噬也被激活。进一步的研究表明，Cezanne通过去泛素化K48-链接泛素化的Lysine 322稳定了PIK3C3。令人惊讶的是，作为PI3P生成的代偿机制，Cezanne通过促进依赖于POLR2A的转录上调了PIK3C2A。基于这些结果，Cezanne还加速了EGFR的回收，这可能解释了Cezanne表达和奥司他替尼耐药性的机制。总之，本研究建立了一个连接Cezanne、自噬和奥司他替尼耐药性的新模型，为探索Cezanne和自噬在LUAD中的作用开辟了新途径。© 2023. 细胞死亡与分化协会 (ADMC)。

Osimertinib is a promising approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treating patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations, however, almost all patients develop resistance to Osimertinib eventually limiting the long-term efficacy. Autophagy is a vital cellular recycling process promoting Osimertinib resistance. Identifying accurate and efficient autophagy-regulatory factors is of great significance in reducing Osimertinib resistance. This study identified Cezanne, a member of the ovarian tumor protease (OTU)-deubiquitinating family, as an autophagy regulator. Cezanne was highly expressed in Osimertinib-resistant cells, and Cezanne overexpression promoted Osimertinib resistance, while chloroquine (CQ), an autophagy inhibitor, reverted this process. In the Cezanne-overexpressing cells, autophagy was activated even in the absence of autophagy inducers rapamycin and Earle's Balanced Salt Solution (EBSS). Further study showed that Cezanne stabilized PIK3C3 by deubiquitinating K48-linked ubiquitination at Lysine 322. Surprisingly, as a compensatory mechanism of PI3P generation, PIK3C2A was shown to be upregulated by Cezanne by promoting its transcription in a POLR2A-dependent way. Based on these results, Cezanne also accelerates EGFR recycling which may explain the mechanism mediating Cezanne expression and Osimertinib resistance. In conclusion, this study establishes a new model connecting Cezanne, autophagy, and Osimertinib resistance, opening new avenues to explore the effect of Cezanne and autophagy in LUAD.© 2023. Cell Death Differentiation Association (ADMC).