期刊
BLOOD
卷 137, 期 20, 页码 2721-2735出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020010167
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资金
- Australian National Health andMedical Research Council (NHMRC) [1016701, 1113577, 1139607, 1140851, 1020363, 1079560, 1156024, 1176175, 1174902, 1157263, 1140906, 1162809, 1086291, 2002618, 2001201]
- Leukemia and Lymphoma Society of America [5467-18]
- Specialized Center of Research [SCOR] grant [7015-18]
- Cure Cancer and Cancer Australia [1186003]
- Victorian Cancer Agency (Mid-career Research Fellowship [MCRF]) [17028]
- MCRF Fellowship [19011, 15018]
- Cancer Council Victoria [1086157, 1147328, 1124178, 1141740]
- Leukaemia Foundation of Australia (the Bill Long Charitable Trust PhDClinical Scholarship)
- Novartis Foundation for Medical-Biological Research
- Swiss National Science Foundation [P400PM-180807]
- Felton Bequest
- Craig Perkins Cancer Research Foundation
- Dyson Bequest
- Medical Research Future Fund [1141460]
- Tour de Cure Foundation [RSP212-2020]
- Australian Cancer Research Foundation
- estate of Anthony (Toni) Redstone OAM
- National Health and Medical Research Council of Australia [1139607, 1156024, 1157263, 1162809, 1174902, 1176175, 2001201, 2002618] Funding Source: NHMRC
- Swiss National Science Foundation (SNF) [P400PM_180807] Funding Source: Swiss National Science Foundation (SNF)
Selective targeting of BCL-2 with BH3-mimetic venetoclax has shown promising results in treating various leukemias. However, for patients with TP53 mutations, a combined BH3-mimetic approach targeting both BCL-2 and MCL-1 proves to be more effective in suppressing leukemia burden. It is crucial to use sufficiently lethal treatment strategies to maximize outcomes for patients with TP53-mutant disease and to avoid the risk of disease progression driven by emergent TP53-mutant clones.
Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.
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