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Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
Richard W Birkinshaw1,2, Jia-Nan Gong3,4, Cindy S Luo3,4
1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia. birkinshaw.r@wehi.edu.au.
Abstract:
Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.
Insights
A new BCL-2 mutation (G101V) causes resistance to venetoclax cancer therapy. Structural studies reveal how this mutation works and suggest new drug designs to overcome resistance in chronic lymphocytic leukemia patients.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Venetoclax is a BCL-2 antagonist targeting apoptosis in cancer.
- Acquired resistance to venetoclax, mediated by BCL-2 mutations like G101V, is observed in chronic lymphocytic leukemia (CLL).
Purpose of the Study:
- To elucidate the molecular mechanisms underlying venetoclax resistance.
- To determine the structural basis of venetoclax interaction with wild-type BCL-2 and the G101V mutant.
Main Methods:
- X-ray crystallography to determine the structures of venetoclax bound to BCL-2 and its G101V mutant.
- Binding assays to assess the affinity of venetoclax to the mutant BCL-2.
Main Results:
- The crystal structure of venetoclax bound to BCL-2 showed subtle differences compared to related compounds.
- The G101V mutation confers resistance through an allosteric effect on residue E152.
- A compensatory E152A mutation restored venetoclax binding, indicating a potential therapeutic strategy.
Conclusions:
- Understanding the structural basis of venetoclax resistance is crucial for developing next-generation inhibitors.
- The findings provide a foundation for designing novel venetoclax analogues effective against BCL-2 mutations in CLL.
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