Open AccessStructures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
Author(s) -
R.W. Birkinshaw,
Jianan Gong,
Chu Luo,
D Lio,
Christine White,
Mary Ann Anderson,
Piers Blombery,
Guillaume Lessène,
Ian J. Majewski,
Rachel Thijssen,
Andrew W. Roberts,
David C.S. Huang,
Peter M. Colman,
P.E. Czabotar
Publication year - 2019
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-019-10363-1
Subject(s) - venetoclax , mutant , mutation , cancer research , apoptosis , drug resistance , computational biology , medicine , genetics , biology , chemistry , chronic lymphocytic leukemia , gene , leukemia
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.