Cancer‐Associated BCL‐2 Mutants Reveal Mechanisms Towards Venetoclax Resistance
Year: 2026
Type: article
Abstract: BCL-2 is an anti-apoptotic protein frequently upregulated in cancer, enabling cell survival despite oncogenic stress. This BCL-2 dependence sensitizes tumor cells to venetoclax, an FDA-approved drug used against chronic lymphocytic leukemia. Yet, treatment-induced mutations in BCL-2 frequently result in resistance. While mutations G101V and D103Y were reported to disrupt BCL-2 interaction with venetoclax, it remains unclear how other mutations cause resistance. Here, we performed a comprehensive comparison of frequently occurring cancer-associated BCL-2 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-apoptotic proteins, revealing a double effect of these mutations. We also define V156D, A113G, R129L, and R139H as previously uncharacterized BCL-2 mutations conferring venetoclax resistance. Remarkably, V156D reduces venetoclax binding allosterically, without altering pro-apoptotic protein inhibition. Other BCL-2 mutants, like A113G, R129L, and R139H, do not exhibit alterations in venetoclax binding, but venetoclax cannot efficiently release their pro-apoptotic partners from inhibitory complexes in cells. Finally, sonrotoclax binds with high affinity to all venetoclax-resistant BCL-2 mutants, yet its efficacy against these BCL-2 mutants in cells was heterogeneous. Our findings uncover diverse mechanisms that reduce venetoclax efficacy with the potential to inform anticancer treatment.
Source: Advanced Science
DOI: 10.1002/advs.76693
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
Awards: Unraveling the molecular mechanisms underlying Ca2+-signaling modulation by CISD2, a wolfram syndrome-associated gene, and its interplay with Bcl-2 (CaCISD2), G2736004587, Exploiting structural insights in IP3 receptor function to develop novel, allosteric inhibitors of IP3 receptor channels (SINFONIC), Bcl-2/IP3R channel structural dynamics underlying complex formation, function and disease (BInamics), 'Mito-tracking’ the phenotyping transition of pancreatic stellate cells, A kinetic, high-throughput cellular screening system (Plate Imaging Reader) for the "real time" monitoring of dynamic intracellular Ca2+ signals in living cells, IP3 receptor modulation by anti-apoptotic Bcl-2: from novel molecular determinants to impact of disease-related mutations, G5492293399, G5552517265, G5653589078, SFB 1218: Regulation der zellulären Funktion durch Mitochondrien, G6430960210, G6818734687, SFB 1403: Zelltod in Immunität, Entzündungen und Erkrankungen, SFB 1530: Aufklärung und Targeting pathogener Mechanismen bei BZellNeoplasien, Bcl-2/Bcl-XL proteins as modulators of calcium signaling through IP3 receptors: from novel molecular mechanisms to implications for therapeutics, IP3 receptor modulation by anti-apoptotic Bcl-2: from novel molecular determinants to impact of disease-related mutations, G8138792450, G8505029525, TRR 353: Regulation von Entscheidungen in Zelltodprozessen, Novel insights in the non-canonical function of anti-apoptotic Bcl-2 proteins in Ca2+ signaling: from channel gating over signaling nanodomains towards cell death
OpenAlex ID: W7170960161