Cotargeting BCL-2 and MCL-1 in high-risk B-ALL
Details
Publication Year 2020-06-23, Volume 4, Issue #12, Page 2762-2767
Journal Title
Blood Advances
Publication Type
Journal Article
Abstract
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.
Publisher
ASH
WEHI Research Division(s)
Chemical Biology; Bioinformatics; Blood Cells And Blood Cancer
PubMed ID
32569380
Open Access at Publisher's Site
https://doi.org/10.1182/bloodadvances.2019001416
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-06-25 07:59:31
Last Modified: 2020-06-25 08:08:07
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