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肾癌中的分子亚群决定了细胞对检查点和血管生成封锁的反应
作者:小柯机器人 发布时间:2020/11/8 21:39:03

美国基因泰克公司Brian Rini和纪念斯隆·凯特琳癌症中心Robert J. Motzer小组合作取得一项新成果。经过不懈努力,他们发现肾癌(RCC)中的分子亚群决定了细胞对检查点和血管生成封锁的反应。这一研究成果在线发表在2020年11月5日的国际学术期刊《癌细胞》上。

通过对823例晚期肾细胞癌患者肿瘤样品的综合多组学评估,研究人员确定了与单独使用血管生成阻断或使用检查点抑制剂产生不同临床结果相关的分子亚群。无偏倚的转录组分析揭示了七个具有不同血管生成、免疫、细胞周期、代谢和基质程序的分子亚群。尽管舒尼替尼和阿替唑珠单抗+贝伐单抗对高血管生成的亚群有效,但阿替唑珠单抗+贝伐单抗改善了高T效应细胞和/或细胞周期转录肿瘤的临床效果。

PBRM1和KDM5C的体细胞突变与高血管生成和AMPK/脂肪酸氧化基因表达有关,而CDKN2A/B和TP53的改变则与细胞周期和合成代谢增加有关。肉瘤样肿瘤具有较低的PBRM1突变和低频血管生成标记物的产生、频繁CDKN2A / B的改变和PD-L1表达增加的特点。

这些发现可用于对患者进行分子分层、解释与单独使用抗血管生成药物相比肉瘤样肿瘤改善的原因,并可实现检查点封锁以及在RCC和其他适应症中研发个性化疗法。

附:英文原文

Title: Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade

Author: Robert J. Motzer, Romain Banchereau, Habib Hamidi, Thomas Powles, David McDermott, Michael B. Atkins, Bernard Escudier, Li-Fen Liu, Ning Leng, Alexander R. Abbas, Jinzhen Fan, Hartmut Koeppen, Jennifer Lin, Susheela Carroll, Kenji Hashimoto, Sanjeev Mariathasan, Marjorie Green, Darren Tayama, Priti S. Hegde, Christina Schiff, Mahrukh A. Huseni, Brian Rini

Issue&Volume: 2020-11-05

Abstract: Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma(RCC) patients identifies molecular subsets associated with differential clinicaloutcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervisedtranscriptomic analysis reveals seven molecular subsets with distinct angiogenesis,immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab +bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumabimproves clinical benefit in tumors with high T-effector and/or cell-cycle transcription.Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, whileCDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoidtumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularlystratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockadeversus antiangiogenics alone, and develop personalized therapies in RCC and otherindications.

DOI: 10.1016/j.ccell.2020.10.011

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30542-0

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx