染色体不稳定（CIN）和随后的非整倍性在各种人类恶性肿瘤中普遍存在，影响肿瘤的进展，例如转移和复发。大量研究表明，高 CIN 肿瘤会出现化疗耐药性，这给治疗带来了重大挑战。鉴于 CIN 与结直肠癌 (CRC) 中观察到的较差预后和抑制的免疫微环境相关，我们的目标是发现对高 CIN CRC 细胞表现出增强抑制作用的化疗药物。通过使用机器学习方法，我们筛选出两种 BCL-XL 抑制剂 Navitoclax 和 WEHI-539 作为 CRC 的 CIN 敏感试剂。随后使用 CIN 非整倍体细胞模型进行的分析证实了高 CIN CRC 细胞对这些药物的脆弱性。我们进一步揭示了 BCL-XL 在高 CIN CRC 细胞活力中的关键作用。此外，为了简化临床中 CIN 水平的评估，我们开发了三基因特征作为 CIN 替代物，以预测 CRC 样本中的预后、化疗和免疫反应。我们的结果证明了 CIN 作为 CRC 治疗靶点的潜在价值，以及 BCL-XL 在调节高 CIN CRC 细胞存活中的重要性，因此代表了将异质性肿瘤细胞的共同特征转化为有效治疗方法的宝贵尝试。 target.© 2024。作者获得中国科学院上海药物研究所和中国药理学会独家许可。

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.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.