基因背景漂移确定药物靶点以减轻癌症治疗耐药性，这一成果由剑桥大学Richard J. Gilbertson研究团队经过不懈努力而取得。2025年6月26日出版的《癌细胞》发表了这项成果。

研究小组通过上下文漂移（RECODR）引入耐药性：这是一种计算管道，将单细胞RNA测序谱的共表达图网络与图嵌入方法相结合，以测量癌症治疗期间基因共表达上下文的变化。RECODR基于基因共表达背景，而不是单独的表达水平，揭示了治疗耐药性的重要信息。对以RECODR为主题的临床前和临床试验中治疗的肿瘤进行分析，揭示了现有计算方法不可见的耐药机制，从而能够设计出针对脉膜丛癌小鼠的高效联合治疗方案，并预测成神经管细胞瘤和三阴性乳腺癌患者的潜在新治疗方案。因此，RECODR可以通过检测决定耐药表型的基因相互作用的环境特异性变化来揭示癌症治疗耐药的复杂性。

据了解，癌症治疗经常失败，因为不同疗法的组合会引起难以预测的复杂耐药机制。

附：英文原文

Title: Gene context drift identifies drug targets to mitigate cancer treatment resistance

Author: Amir Jassim, Birgit V. Nimmervoll, Sabrina Terranova, Erica Nathan, Linda Hu, Jessica T. Taylor, Katherine E. Masih, Lisa Ruff, Matilde Duarte, Elizabeth Cooper, Gunjan Katyal, Melika Akhbari, Reuben J. Gilbertson, Jennifer C. Coleman, Joseph S. Toker, Colton Terhune, Gabriel Balmus, Stephen P. Jackson, Hailong Liu, Tao Jiang, Michael D. Taylor, Kui Hua, Jean E. Abraham, Mariella G. Filbin, Anthony Hill, Anarita Patrizi, Neil Dani, Aviv Regev, Maria K. Lehtinen, Richard J. Gilbertson

Issue&Volume: 2025-06-26

Abstract: Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms –invisible to existing computational approaches– enabling the design of highly effective combination treatments for mice with choroid plexus carcinoma, and the prediction of potential new treatments for patients with medulloblastoma and triple-negative breast cancer. Thus, RECODR may unravel the complexity of cancer treatment resistance by detecting context-specific changes in gene interactions that determine the resistant phenotype.

DOI: 10.1016/j.ccell.2025.06.005

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00255-7