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Cancer-Associated BCL-2 Mutants Reveal Mechanisms Towards Venetoclax Resistance
Jonas Aufdermauer1,2, Ian de de Ridder3, Mahjoobeh Ehsani4
1Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 24, 2026
Summary
Cancer drug resistance arises from BCL-2 mutations that disrupt venetoclax binding or protein interactions. Understanding these diverse resistance mechanisms is key to developing new anticancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- BCL-2 is an anti-apoptotic protein crucial for cancer cell survival.
- Venetoclax targets BCL-2 but resistance often develops due to mutations.
- Mechanisms of BCL-2-mediated venetoclax resistance are not fully understood.
Purpose of the Study:
- To comprehensively analyze cancer-associated BCL-2 mutations and their impact on venetoclax resistance.
- To elucidate the diverse molecular mechanisms underlying BCL-2 mutations conferring drug resistance.
- To evaluate the efficacy of sonrotoclax against venetoclax-resistant BCL-2 mutants.
Main Methods:
- Comparative analysis of BCL-2 mutations within and outside the venetoclax binding site.
- Assessment of BCL-2 interaction with venetoclax and pro-apoptotic proteins.
- In vitro and cellular assays to determine drug resistance profiles.
Main Results:
- Mutations G101V and D103Y disrupt venetoclax binding and enhance inhibition of pro-apoptotic proteins.
- V156D, A113G, R129L, and R139H are novel BCL-2 mutations conferring venetoclax resistance.
- V156D causes allosteric resistance; A113G, R129L, R139H impair drug-induced release of pro-apoptotic partners.
- Sonrotoclax shows high affinity for resistant mutants but heterogeneous cellular efficacy.
Conclusions:
- BCL-2 mutations confer venetoclax resistance through multiple distinct mechanisms.
- Understanding these mechanisms is crucial for overcoming drug resistance in cancer.
- Targeted therapies may need to be tailored based on specific resistance mutations.
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