Cotargeting BCL-2 and MCL-1 in high-risk B-ALL
AuthorMoujalled, DM; Hanna, DT; Hediyeh-zadeh, S; Pomilio, G; Brown, L; Litalien, V; Bartolo, R; Fleming, S; Chanrion, M; Banquet, S; ...
Source TitleBLOOD ADVANCES
PublisherAMER SOC HEMATOLOGY
University of Melbourne Author/sNg, Ashley; Lessene, Guillaume; Roberts, Andrew; Ekert, Paul; Davis, Melissa; Khaw, Seong; Huang, David; White, Christine
AffiliationMedical Biology (W.E.H.I.)
Centre for Cancer Research
Biochemistry and Molecular Biology
Document TypeJournal Article
CitationsMoujalled, D. M., Hanna, D. T., Hediyeh-zadeh, S., Pomilio, G., Brown, L., Litalien, V., Bartolo, R., Fleming, S., Chanrion, M., Banquet, S., Maragno, A. -L., Kraus-Berthier, L., Schoumacher, M., Mullighan, C. G., Georgiou, A., White, C. A., Lessene, G., Huang, D. C. S., Roberts, A. W. ,... Khaw, S. L. (2020). Cotargeting BCL-2 and MCL-1 in high-risk B-ALL. BLOOD ADVANCES, 4 (12), pp.2762-2767. https://doi.org/10.1182/bloodadvances.2019001416.
Access StatusOpen Access
Open Access URLhttps://doi.org/10.1182/bloodadvances.2019001416
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322969
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.
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