美国西南医学中心Ping Mu小组的最新研究表明，SYNCRIP缺失造成APOBEC-诱导的前列腺癌（PCa）产生、肿瘤异质性和雄激素受体（AR）靶向治疗耐药性。相关论文发表在2023年7月20日出版的《癌细胞》杂志上。

研究人员发现SYNCRIP是抑制APOBEC诱导前列腺癌突变的内源性分子制动器。在SYNCRIP缺失的PCa细胞中，过度激活的APOBEC3B是一种关键的突变体，其是PCa中一些经常突变基因（包括FOXA1、EP300）的分子原动力。功能筛查表明PCa中AR靶向治疗耐药性的八个关键驱动基因：BRD7、CBX8、EP300、FOXA1、HDAC5、HSF4、STAT3和AR，这些驱动基因的突变由APOBEC3B介导。该研究结果揭示了APOBEC驱动诱变的细胞内在机制，该机制在PCa AR靶向治疗耐药性中起重要作用。

研究人员表示，肿瘤突变负荷和异质性会加剧肿瘤对许多靶向治疗的耐药性。胞嘧啶脱氨酶APOBEC蛋白与70多种人类癌症的突变特征有关。然而，癌细胞如何劫持APOBEC介导的诱变以促进肿瘤异质性进而加剧治疗耐药性的机制尚不清楚。

附：英文原文

Title: Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer

Author: Xiaoling Li, Yunguan Wang, Su Deng, Guanghui Zhu, Choushi Wang, Nickolas A. Johnson, Zeda Zhang, Carla Rodriguez Tirado, Yaru Xu, Lauren A. Metang, Julisa Gonzalez, Atreyi Mukherji, Jianfeng Ye, Yuqiu Yang, Wei Peng, Yitao Tang, Mia Hofstad, Zhiqun Xie, Heewon Yoon, Liping Chen, Xihui Liu, Sujun Chen, Hong Zhu, Douglas Strand, Han Liang, Ganesh Raj, Housheng Hansen He, Joshua T. Mendell, Bo Li, Tao Wang, Ping Mu

Issue&Volume: 2023-07-20

Abstract: Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies. The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer (PCa). Overactivated APOBEC3B, in SYNCRIP-deficient PCa cells, is a key mutator, representing the molecular source of driver mutations in some frequently mutated genes in PCa, including FOXA1, EP300. Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.

DOI: 10.1016/j.ccell.2023.06.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00235-0