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Evasion of programmed cell death (apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro\u2010survival 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Here we explored the role of <jats:italic>BCL2L1<\/jats:italic> and the encoded anti\u2010apoptotic BCL\u2010XL in GC. Using Droplet Digital PCR (ddPCR) technology to investigate the DNA amplification of <jats:italic>BCL2L1<\/jats:italic> in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL\u2010XL inhibitors A1155463 and A1331852, pan\u2010inhibitor ABT\u2010263, and VHL\u2010based PROTAC\u2010BCL\u2010XL was analyzed using (CellTiter\u2010Glo) 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\u2010BCL\u2010XL kills GC cells. Co\u2010immunoprecipitation (Co\u2010IP) was used to investigate the mechanism of A1331852 and ABT\u2010263 kills GC cell lines. DDPCR, WB, and real\u2010time PCR (RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The functional assay showed that a subset of GC cell lines relies on BCL\u2010XL for survival. In gastric cancer cell lines, BCL\u2010XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT\u2010263, indicating that ABT\u2010263 is not an optimal inhibitor of BCL\u2010XL. VHL\u2010based PROTAC\u2010BCL\u2010XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time\u2010 and dose\u2010dependent manner through the proteasome pathway. Statistical analysis showed that the BCL\u2010XL protein level predicts the response of GC cells to BCL\u2010XL targeting therapy and <jats:italic>BCL2L1<\/jats:italic> gene CNVs do not reliably predict BCL\u2010XL expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified BCL\u2010XL as a promising therapeutic target in a subset of GC cases with high levels of BCL\u2010XL protein expression. Functionally, we demonstrated that both selective BCL\u2010XL inhibitors and VHL\u2010based PROTAC BCL\u2010XL can potently kill GC cells that are reliant on BCL\u2010XL for survival. However, we found that <jats:italic>BCL2L1<\/jats:italic> copy number variations (CNVs) cannot reliably predict BCL\u2010XL expression, but the BCL\u2010XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL\u2010XL\u2010targeting compounds. Taken together, our study pinpointed BCL\u2010XL as potential druggable target for specific subsets of GC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ame2.12330","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T18:46:10Z","timestamp":1686163570000},"page":"245-254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Anti\u2010apoptotic protein BCL\u2010XL as a therapeutic vulnerability in gastric cancer"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5176-8026","authenticated-orcid":false,"given":"Yumin","family":"Wei","sequence":"first","affiliation":[{"name":"National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for 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Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guomin","family":"Xie","sequence":"additional","affiliation":[{"name":"National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases  Beijing China"},{"name":"Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjiu","family":"Yang","sequence":"additional","affiliation":[{"name":"National Human Diseases Animal Model Resource Center, The Institute of Laboratory Animal Science Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing China"},{"name":"NHC Key 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