Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia.

Abstract

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance.See related commentary by Thangavadivel and Byrd, p. 320.This article is highlighted in the In This Issue feature, p. 305.

• Authors: Piers Blombery, Mary Ann Anderson, Jia-Nan Gong, Rachel Thijssen, Richard W Birkinshaw, Ella R Thompson, Charis E Teh, Tamia Nguyen, Zhen Xu, Christoffer Flensburg, Thomas E Lew, Ian J Majewski, Daniel H D Gray, David A Westerman, Constantine S Tam, John F Seymour, Peter E Czabotar, David C S Huang, Andrew W Roberts
• Journal: Cancer discovery (Cancer Discov) Vol. 9 Issue 3 Pg. 342-353 (03 2019) ISSN: 2159-8290 [Electronic] United States
• PMID: 30514704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• venetoclax

Topics

• Antineoplastic Agents (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• High-Throughput Nucleotide Sequencing
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics, pathology)
• Models, Molecular
• Mutation
• Neoplasm Recurrence, Local (drug therapy, genetics, pathology)
• Protein Conformation
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured