Cotargeting BCL-2 and MCL-1 in high-risk B-ALL

Moujalled, DM; Hanna, DT; Hediyeh-Zadeh, S; Pomilio, G; BROWN, L; Litalien, V; Bartolo, R; Fleming, S; Chanrion, M; Banquet, S; Maragno, AL; Kraus-Berthier, L; Schoumacher, M; Mullighan, CG; Georgiou, A; White, CA; Lessene, G; Huang, DCS; Roberts, AW; Geneste, O; Rasmussen, L; Davis, MJ; Ekert, PG; Wei, A; Ng, AP; Khaw, SL

Author(s): Moujalled, DM; Hanna, DT; Hediyeh-Zadeh, S; Pomilio, G; BROWN, L; Litalien, V; Bartolo, R; Fleming, S; Chanrion, M; Banquet, S; Maragno, AL; Kraus-Berthier, L; Schoumacher, M; Mullighan, CG; Georgiou, A; White, CA; Lessene, G; Huang, DCS; Roberts, AW; Geneste, O; Rasmussen, L; Davis, MJ; Ekert, PG; Wei, A; Ng, AP; Khaw, SL;
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
Research Division(s): Chemical Biology; Bioinformatics; Blood Cells And Blood Cancer
PubMed ID: 32569380
Publisher's Version: https://doi.org/10.1182/bloodadvances.2019001416
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2019001416
NHMRC Grants: NHMRC/GNT1113577, NHMRC/1060179, NHMRC/GNT1122783,
Terms of Use/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