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 pathobiol-ogy of venetoclax resistance and provides a potential biomarker of impending clinical relapse.
| Original language | English |
|---|---|
| Pages (from-to) | 342-353 |
| Number of pages | 12 |
| Journal | Cancer discovery |
| Volume | 9 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Mar 2019 |
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In: Cancer discovery, Vol. 9, No. 3, 01.03.2019, p. 342-353.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia
AU - Blombery, Piers
AU - Anderson, Mary Ann
AU - Gong, Jia Nan
AU - Thijssen, Rachel
AU - Birkinshaw, Richard W.
AU - Thompson, Ella R.
AU - Teh, Charis E.
AU - Nguyen, Tamia
AU - Xu, Zhen
AU - Flensburg, Christoffer
AU - Lew, Thomas E.
AU - Majewski, Ian J.
AU - Gray, Daniel H.D.
AU - Westerman, David A.
AU - Tam, Constantine S.
AU - Seymour, John F.
AU - Czabotar, Peter E.
AU - Huang, David C.S.
AU - Roberts, Andrew W.
N1 - Funding Information: The authors are grateful to the patients who enrolled on the venetoclax clinical trials, and for assistance from Naomi Sprigg with collection and curation of samples, Dr. Andrew Mitchell for mass cytometry maintenance/operation, and Tania Tan for sample preparation for mass cytometry. The mass cytometry was performed in part at the Materials Characterisation and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility. This research was supported by grants from the Snowdome Foundation (P. Blombery and M.A. Anderson), Vision Super and the Wilson Centre of Lymphoma Genomics (P. Blombery), the Leukemia and Lymphoma Society [fellowship to R. Thijssen (5467-18); SCOR (7015-18) to D.C.S. Huang and A.W. Rob-erts], the Cancer Council of Victoria (grants 1146518 and 1102104 to D.H.D. Gray; 1124178 to I.J. Majewski), the Victorian Cancer Agency (fellowship to I.J. Majewski), the CLL Global Foundation (C.S. Tam), the National Health and Medical Research Council (NHMRC) of Australia [fellowships to C.E. Teh (1089072), D.H.D. Gray (1090236), P.E. Czabotar (1079700), D.C.S. Huang (1043149), and A.W. Roberts (1079560)], and grants to P.E. Czabotar (project 1141874), D.C.S. Huang (program 1113133), and A.W. Roberts (program 1113577). This work was made possible through Victorian State Government Operational Infrastructure Support, Australian Government NHMRC IRIISS, and financial support for mass cytometry by the Victorian Comprehensive Cancer Centre. Funding Information: The Walter and Eliza Hall Institute receives milestone and royalty payments related to venetoclax, and employees may be eligible for benefits related to these payments. M.A. Anderson is a hematologist at the Department of Haematology, Royal Melbourne Hospital and Peter McCallum Cancer Centre; is an employee of the Walter and Eliza Hall Institute which receives milestone and royalty payments related to venetoclax; and has received honoraria from the speakers bureau of AbbVie. J.-n. Gong, R. Thijssen, R.W. Birkinshaw, C.E. Teh, Z. Xu, C. Flensburg, and I.J. Majewski have received remuneration from the Walter and Eliza Hall Institute. T.E. Lew is an employee of the Walter and Eliza Hall Institute of Medical Research and receives milestone and royalty payments related to venetoclax. D.H.D. Gray reports receiving commercial research support from Servier Pharmaceuticals and has received other remuneration from the Walter and Eliza Hall Institute. C.S. Tam has received honoraria from the speakers bureau of AbbVie. J.F. Seymour reports receiving commercial research support from AbbVie, Celgene, Janssen, and Roche; has received honoraria from the speakers bureaus of AbbVie and Roche; and is a consultant/advisory board member for AbbVie, Acerta, Celgene, Janssen, Morphosys, Roche, Sunesis, and Takeda. P.E. Czabotar reports receiving a commercial research grant from Anaxis, is a consultant/advisory board member for Anaxis, and has received other remuneration from the Walter and Eliza Hall Institute. D.C.S. Huang reports receiving a commercial research grant from Servier, has received honoraria from the speakers bureau of AbbVie, and has received other remuneration from the Walter and Eliza Hall Institute of Medical Research. A.W. Roberts receives milestones and royalties related to venetoclax from the Walter and Eliza Hall Institute of Funding Information: The authors are grateful to the patients who enrolled on the venetoclax clinical trials, and for assistance from Naomi Sprigg with collection and curation of samples, Dr. Andrew Mitchell for mass cytometry maintenance/operation, and Tania Tan for sample preparation for mass cytometry. The mass cytometry was performed in part at the Materials Characterisation and Fabrication Platform at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility. This research was supported by grants from the Snowdome Foundation (P. Blombery and M.A. Anderson), Vision Super and the Wilson Centre of Lymphoma Genomics (P. Blombery), the Leukemia and Lymphoma Society [fellowship to R. Thijssen (5467-18); SCOR (7015-18) to D.C.S. Huang and A.W. Roberts], the Cancer Council of Victoria (grants 1146518 and 1102104 to D.H.D. Gray; 1124178 to I.J. Majewski), the Victorian Cancer Agency (fellowship to I.J. Majewski), the CLL Global Foundation (C.S. Tam), the National Health and Medical Research Council (NHMRC) of Australia [fellowships to C.E. Teh (1089072), D.H.D. Gray (1090236), P.E. Czabotar (1079700), D.C.S. Huang (1043149), and A.W. Roberts (1079560)], and grants to P.E. Czabotar (project 1141874), D.C.S. Huang (program 1113133), and A.W. Roberts (program 1113577). This work was made possible through Victorian State Government Operational Infrastructure Support, Australian Government NHMRC IRIISS, and financial support for mass cytometry by the Victorian Comprehensive Cancer Centre. Funding Information: Medical Research, reports receiving commercial research grants from AbbVie and Janssen, and has received other remuneration from the Walter and Eliza Hall Institute of Medical Research. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: © 2018 American Association for Cancer Research.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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 pathobiol-ogy of venetoclax resistance and provides a potential biomarker of impending clinical relapse.
AB - 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 pathobiol-ogy of venetoclax resistance and provides a potential biomarker of impending clinical relapse.
UR - http://www.scopus.com/inward/record.url?scp=85062793185&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/2159-8290.CD-18-1119
DO - https://doi.org/10.1158/2159-8290.CD-18-1119
M3 - Article
C2 - 30514704
SN - 2159-8274
VL - 9
SP - 342
EP - 353
JO - Cancer discovery
JF - Cancer discovery
IS - 3
ER -