TY - JOUR
T1 - Cotargeting BCL-2 and MCL-1 in high-risk B-ALL
AU - Moujalled, Donia M.
AU - Hanna, Diane T.
AU - Hediyeh-Zadeh, Soroor
AU - Pomilio, Giovanna
AU - Brown, Lauren
AU - Litalien, Veronique
AU - Bartolo, Ray
AU - Fleming, Shaun
AU - Chanrion, Maïa
AU - Banquet, Sébastien
AU - Maragno, Ana Leticia
AU - Kraus-Berthier, Laurence
AU - Schoumacher, Marie
AU - Mullighan, Charles G.
AU - Georgiou, Angela
AU - White, Christine A.
AU - Lessene, Guillaume
AU - Huang, David C.S.
AU - Roberts, Andrew W.
AU - Geneste, Olivier
AU - Rasmussen, Lorna
AU - Davis, Melissa J.
AU - Ekert, Paul G.
AU - Wei, Andrew
AU - Ng, Ashley P.
AU - Khaw, Seong L.
N1 - Funding Information:
Conflict-of-interest disclosure: A.G., A.P.N., A.W.R., C.A.W., D.C.S.H., G.L., S.H.-z., and M.J.D. are employees of the Walter and Eliza Hall Institute, which receives milestone and royalty payments related to venetoclax. A.W., D.M.M., and P.G.E. receive royalty payments related to venetoclax. A.W., A.W.R., D.M.M., and G.L. have received research funding from Servier. A.P.N., A.W.R., D.C.S.H., G.L., S.H.-z., S.L.K., and M.J.D. are recipients of a share in royalty payments paid to the Walter and Eliza Hall Institute of Medical Research. A.W.R. has received research funding from AbbVie, Genentech, Janssen, and BeiGene. C.G.M. has received research funding from AbbVie, Pfizer, Loxo Oncology, Amgen, and Illumina. G.L. has received research funding from Genentech and Anaxis Pharma. S.L.K. has received research funding from AbbVie, Novartis, Jazz Pharmaceuticals, and Bristol-Myers Squibb. A.-L.M., M.S., O.G., and S.B. are employees of Servier. The remaining authors declare no competing financial interests.
Funding Information:
This work was supported by the National Health and Medical Research Council program grant GNT1113577 (A.W.R.), project grants GNT1060179 and GNT1122783 (A.P.N.), Cancer Council Victoria, Victorian Cancer Agency, Leukaemia Foundation of Australia, Leukemia and Lymphoma Society (Specialized Center of Research) grant 20454683, Australian Cancer Research Foundation, Monash Partners, the Alfred Foundation, and the Medical Research Future Fund, Children’s Cancer Foundation, The Department of Health and Human Services through the Victorian Cancer Agency (S.L.K.), as well as by philanthropic support from the Walter and Eliza Hall Institute, and operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme and the Victorian Government Operational Infrastructure Support. This work has received funding support from Servier.
Publisher Copyright:
© 2020 by The American Society of Hematology.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/23
Y1 - 2020/6/23
N2 - Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3- mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
AB - Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has a poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab and chimeric antigen receptor T cells. Targeting aberrant cell survival pathways with selective small molecule BH3-mimetic inhibitors of BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is an emerging therapeutic option. We report that combined targeting of BCL-2 and MCL1 is synergistic in B-ALL in vitro. The combination demonstrated greater efficacy than standard chemotherapeutics and TKIs in primary samples from adult B-ALL with Ph+ ALL, Ph-like ALL, and other B-ALL. Moreover, combined BCL-2 or MCL1 inhibition with dasatinib showed potent killing in primary Ph+ B-ALL cases, but the BH3-mimetic combination appeared superior in vitro in a variety of Ph-like ALL samples. In PDX models, combined BCL-2 and MCL1 targeting eradicated ALL from Ph- and Ph+ B-ALL cases, although fatal tumor lysis was observed in some instances of high tumor burden. We conclude that a dual BH3- mimetic approach is highly effective in diverse models of high-risk human B-ALL and warrants assessment in clinical trials that incorporate tumor lysis precautions.
UR - http://www.scopus.com/inward/record.url?scp=85086943107&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2019001416
DO - 10.1182/bloodadvances.2019001416
M3 - Article
C2 - 32569380
AN - SCOPUS:85086943107
SN - 2473-9529
VL - 4
SP - 2762
EP - 2767
JO - Blood Advances
JF - Blood Advances
IS - 12
ER -
