Tsvetkov Peter, Sokol Ethan, Jin Dexter, Brune Zarina, Thiru Prathapan, Ghandi Mahmoud, Garraway Levi A, Gupta Piyush B, Santagata Sandro, Whitesell Luke, Lindquist Susan
Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):382-387. doi: 10.1073/pnas.1619067114. Epub 2016 Dec 27.
The use of proteasome inhibitors to target cancer's dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers.
蛋白酶体抑制剂用于靶向癌症对改变的蛋白质稳态的依赖性，这一应用在很大程度上受到内在抗性和获得性抗性的限制。通过分析来自数千个癌细胞系和肿瘤的数据，我们发现那些一个或多个19S蛋白酶体亚基表达受抑制的细胞系和肿瘤表现出对蛋白酶体抑制剂的内在抗性。此外，这种蛋白酶体亚基抑制与骨髓瘤患者的不良预后相关，而蛋白酶体抑制剂是骨髓瘤治疗的主要手段。除了赋予对蛋白酶体抑制剂的抗性外，蛋白酶体亚基抑制还标志着转录组更广泛重塑的一个信号。这种重塑产生了独特的基因特征以及对促凋亡药物ABT-263的新的易感性。19S调节复合物组成中这种频繁出现的、自然产生的失衡是通过多种机制实现的，包括DNA甲基化，并标志着在多种癌症中出现了一种可遗传改变的、与治疗相关的状态。
