澳大利亚沃尔特和伊丽莎·霍尔医学研究所Gemma L. Kelly团队将STING重新引入BH3拟似药物，用于TP53突变的血液癌治疗。2024年4月25日，国际知名学术期刊《癌细胞》发表了这一成果。

研究人员报道p53在BH3拟似药物诱导的线粒体外膜渗透作用后被激活，导致仅BH3蛋白的诱导，从而增强促凋亡信号。缺乏TP53的淋巴瘤缺乏这种前反馈回路，在BH3拟似药物治疗后提供了生存和疾病复发的机会。

TP53缺陷造成的治疗障碍可以通过直接激活cGAS/STING通路来克服，cGAS/STING通路通过不依赖于p53的BH3蛋白上调来促进血癌细胞凋亡。临床相关STING激动剂与BH3拟似药物联合，有效杀伤TRP53/ TP53突变型小鼠B淋巴瘤、人NK/T淋巴瘤和急性髓系白血病细胞。这代表了一种很有前景的治疗方案，可以在临床上快速治疗TP53突变型血癌。

研究人员表示，TP53突变型血癌仍然是一个临床挑战。BH3拟似药物抑制BCL-2促生存蛋白，诱导癌细胞凋亡。尽管作用于p53的下游，但功能性p53是BH3拟似药物通过未知机制最大限度杀死癌细胞所必需的。

附：英文原文

Title: Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers

Author: Sarah T. Diepstraten, Yin Yuan, John E. La Marca, Savannah Young, Catherine Chang, Lauren Whelan, Aisling M. Ross, Karla C. Fischer, Giovanna Pomilio, Rhiannon Morris, Angela Georgiou, Veronique Litalien, Fiona C. Brown, Andrew W. Roberts, Andreas Strasser, Andrew H. Wei, Gemma L. Kelly

Issue&Volume: 2024-04-25

Abstract: TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.

DOI: 10.1016/j.ccell.2024.04.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00128-4