Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.
Bridged Bicyclo Compounds, Heterocyclic
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Leukemia, Myeloid, Acute
/ drug therapy
MAP Kinase Signaling System
/ drug effects
Myeloid Cell Leukemia Sequence 1 Protein
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Sulfonamides
/ pharmacology
ras Proteins
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
21 02 2022
21 02 2022
Historique:
received:
13
10
2020
accepted:
20
12
2021
revised:
01
11
2021
entrez:
21
2
2022
pubmed:
22
2
2022
medline:
5
4
2022
Statut:
epublish
Résumé
Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.
Identifiants
pubmed: 35185150
doi: 10.1038/s41392-021-00870-3
pii: 10.1038/s41392-021-00870-3
pmc: PMC8858957
doi:
Substances chimiques
BCL2 protein, human
0
Bridged Bicyclo Compounds, Heterocyclic
0
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
Sulfonamides
0
ras Proteins
EC 3.6.5.2
venetoclax
N54AIC43PW
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
51Subventions
Organisme : NCI NIH HHS
ID : R35 CA242427
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA235622
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100632
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224019
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA066996
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262758
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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