Pan-RAF inhibition induces apoptosis in acute myeloid leukemia cells and synergizes with BCL2 inhibition

被引:19
|
作者
Tambe, Mahesh [1 ]
Karjalainen, Ella [1 ]
Vaha-Koskela, Markus [1 ]
Bulanova, Daria [1 ,2 ,3 ]
Gjertsen, Bjorn T. [4 ,5 ]
Kontro, Mika [6 ,7 ]
Porkka, Kimmo [6 ,7 ]
Heckman, Caroline A. [1 ]
Wennerberg, Krister [1 ,2 ,3 ]
机构
[1] Univ Helsinki, Inst Mol Med Finland, Helsinki Inst Life Sci, Helsinki, Finland
[2] Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, Copenhagen, Denmark
[3] Univ Copenhagen, Novo Nordisk Fdn Ctr Stem Cell Biol DanStem, Copenhagen, Denmark
[4] Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, Bergen, Norway
[5] Haukeland Hosp, Dept Internal Med, Hematol Sect, Bergen, Norway
[6] Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland
[7] Helsinki Univ Cent Hosp, Comprehens Canc Ctr, Helsinki, Finland
基金
芬兰科学院;
关键词
ACUTE MYELOGENOUS LEUKEMIA; KINASE; LY3009120; MEK; INDUCTION; STRATEGY; PATHWAY; MODELS; MCL-1; BRAF;
D O I
10.1038/s41375-020-0972-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Pan-RAF inhibitors have shown promise as antitumor agents inRASandRAFmutated solid cancers. However, the efficacy of pan-RAF inhibitors in acute myeloid leukemia (AML) has not previously been explored. In AML, the RAS-RAF-MEK-ERK (MAPK) pathway is one of the most aberrantly activated oncogenic pathways, but previous targeting of this pathway by MEK inhibitors has not proven effective in clinical trials. Here we show that pan-RAF inhibition, but not MEK inhibition, induced cell death in 29% of AML samples while being nontoxic toward healthy bone marrow cells. Mechanistically, pan-RAF inhibition downregulated MCL1 protein synthesis and induced apoptosis in cells dependent on MCL1 for their survival. Furthermore, the combination of a pan-RAF and a BCL2 inhibitor overcame resistance to either compound alone in AML cell lines, as well as synergized and induced long-term responses ex vivo in AML patient samples relapsed or refractory to azacitidine + venetoclax treatment. Together, our results indicate that pan-RAF inhibition, alone or in combination with BCL2 inhibition, is a promising treatment strategy for AML.
引用
收藏
页码:3186 / 3196
页数:11
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