DOI: 10.1002/ame2.12330
Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer
Yumin Wei1
Liping Zhang1
Chao Wang1
Zefeng Li2
Mingjie Luo3
Guomin Xie1
Xingjiu Yang1
Mengyuan Li1
Shuyue Ren1
Dongbing Zhao2
Ran Gao1
Jia-Nan Gong1
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;NHC Key Laboratory of Human Disease Comparative Medicine,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases,Beijing,China;Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases,Beijing,China2.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,China3.State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-Sen University,Guangzhou,China
摘要：Background:New therapeutic targets are needed to improve the outcomes for gas-tric 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 under-pinning 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 ampli-fication 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 mem-bers in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells.Co-immunoprecipitation(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 ap-pears 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 anal-ysis 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 of GC cases with high levels of BCL-XL protein expression.Functionally,we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival.However,we found that BCL2L1 copy number variations(CNVs)cannot reliably predict BCL-XL expression,but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds.Taken together,our study pinpointed BCL-XL as poten-tial druggable target for specific subsets of GC.
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论文发表日期：2023-06-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：10( 245-254 )
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