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

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

机构地区：[1]Institute of Translational Medicine,Medical College,Yangzhou University,Yangzhou,225001,China [2]Clinical Medical College,Yangzhou University,Yangzhou,225009,China [3]Jiangsu Key Laboratory of Experimental&Translational Non-coding RNA Research,Yangzhou,225001,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2420-2431,共12页中国药理学报（英文版）

基　　金：support of the“Youth Talent Support Program”from Yangzhou University.This work was supported by the National Natural Science Foundation of China(81972251 to XF and 32170552 to YZ);Natural Science Research of Jiangsu Higher Education Institutions of China(23KJA310012 to XF and 21KJA180001 to YZ);the Jiangsu Provincial Medical Key Discipline Cultivation Unit(JSDW202251).

摘　　要：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.

关 键 词：colorectal carcinoma chromosome instability CHEMOSENSITIVITY BCL-XL Navitoclax WEHI-539 

分 类 号：R735.35[医药卫生—肿瘤]