Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer  

作　　者：Yumin Wei Liping Zhang Chao Wang Zefeng Li Mingjie Luo Guomin Xie Xingjiu Yang Mengyuan Li Shuyue Ren Dongbing Zhao Ran Gao Jia-Nan Gong 

机构地区：[1]National Human Diseases Animal Model Resource Center,The Institute of Laboratory Animal Science,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing,China [2]NHC Key Laboratory of Human Disease Comparative Medicine,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases,Beijing,China [3]Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases,Beijing,China [4]Department of Pancreatic and Gastric Surgical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China [5]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-Sen University,Guangzhou,China

出　　处：《Animal Models and Experimental Medicine》2023年第3期245-254,共10页动物模型与实验医学（英文）

摘　　要：Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset o

关 键 词：apoptosis BCL2L1(BCL-XL) gastric cancer(GC) PROTAC-BCL-XL selective BCL-XL inhibitors 

分 类 号：R735.2[医药卫生—肿瘤]