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This BCL\u20102 dependence sensitizes tumor cells to venetoclax, an FDA\u2010approved drug used against chronic lymphocytic leukemia. Yet, treatment\u2010induced mutations in BCL\u20102 frequently result in resistance. While mutations G101V and D103Y were reported to disrupt BCL\u20102 interaction with venetoclax, it remains unclear how other mutations cause resistance. Here, we performed a comprehensive comparison of frequently occurring cancer\u2010associated BCL\u20102 mutations inside and outside the venetoclax binding site. We find that, besides disrupting venetoclax interaction, G101V and D103Y also increased the sequestration and inhibition of pro\u2010apoptotic proteins, revealing a double effect of these mutations. We also define V156D, A113G, R129L, and R139H as previously uncharacterized BCL\u20102 mutations conferring venetoclax resistance. Remarkably, V156D reduces venetoclax binding allosterically, without altering pro\u2010apoptotic protein inhibition. Other BCL\u20102 mutants, like A113G, R129L, and R139H, do not exhibit alterations in venetoclax binding, but venetoclax cannot efficiently release their pro\u2010apoptotic partners from inhibitory complexes in cells. Finally, sonrotoclax binds with high affinity to all venetoclax\u2010resistant BCL\u20102 mutants, yet its efficacy against these BCL\u20102 mutants in cells was heterogeneous. Our findings uncover diverse mechanisms that reduce venetoclax efficacy with the potential to inform anticancer treatment.<\/jats:p>","DOI":"10.1002\/advs.76693","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:20:01Z","timestamp":1784895601000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cancer\u2010Associated BCL\u20102 Mutants Reveal Mechanisms Towards Venetoclax Resistance"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7028-1135","authenticated-orcid":false,"given":"Jonas","family":"Aufdermauer","sequence":"first","affiliation":[{"name":"Cologne Excellence Cluster on Cellular Stress Responses in Aging\u2010Associated Diseases University of Cologne  Cologne Germany"},{"name":"Department of Membrane Dynamics Max Planck Institute of Biophysics  Frankfurt am Main 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