Centre for Cancer Research - Research Publications

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Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

Birkinshaw, RW ; Gong, J-N ; Luo, CS ; Lio, D ; White, CA ; Anderson, MA ; Blombery, P ; Lessene, G ; Majewski, IJ ; Thijssen, R ; Roberts, AW ; Huang, DCS ; Colman, PM ; Czabotar, PE (NATURE PUBLISHING GROUP, 2019-06-03)

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.