扬州大学赵雅研究组发现，染色体不稳定性通过增强对BCL-XL抑制剂的化疗敏感性在结直肠癌中发挥潜在的治疗参考。相关论文于2024年8月26日在线发表在《中国药理学报》杂志上。

研究人员表示，染色体不稳定性（CIN）及其导致的非整倍性在多种人类恶性肿瘤中普遍存在，并影响肿瘤的进展，如转移和复发。大量研究表明，高CIN肿瘤易发展出化疗耐药性，这给治疗带来了显著挑战。

鉴于CIN与结直肠癌（CRC）预后较差及免疫微环境受抑制的关联性，研究人员旨在发现对高CIN CRC细胞具有增强抑制作用的化疗药物。通过机器学习方法，研究人员筛选出了两种CIN敏感的BCL-XL抑制剂——Navitoclax和WEHI-539。随后利用CIN-非整倍性细胞模型的分析证实了高CIN CRC细胞对这些药物的脆弱性。

研究人员进一步揭示了BCL-XL在维持高CIN CRC细胞生存中的关键作用。此外，为了简化临床中CIN水平的评估，研究人员开发了一个由三个基因组成的特征作为CIN的替代指标，用于预测CRC样本的预后、化疗反应和免疫反应。这些研究结果表明，CIN在CRC治疗中作为治疗靶点的潜在价值，以及BCL-XL在调控高CIN CRC细胞存活中的重要性，从而代表了一种将异质性肿瘤细胞的共同特征转化为有效治疗靶点的有益尝试。

附：英文原文

Title: Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma

Author: Fang, Xiao, Yu, Wen-ying, Zhu, Chun-miao, Zhao, Nan, Zhao, Wei, Xie, Ting-ting, Wei, Li-jie, Sun, Xi-ran, Xie, Juan, Zhao, Ya

Issue&Volume: 2024-08-26

Abstract: Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.

DOI: 10.1038/s41401-024-01372-y

Source: https://www.nature.com/articles/s41401-024-01372-y