Combined MEK and BCL-2/X
Aniline Compounds
/ pharmacology
Animals
Apoptosis
/ drug effects
Bcl-2-Like Protein 11
/ genetics
Cell Line, Tumor
Cystadenocarcinoma, Serous
/ drug therapy
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Heterografts
Humans
MAP Kinase Signaling System
/ drug effects
Mice
Neoplasm Grading
Neoplasm Recurrence, Local
/ drug therapy
Ovarian Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Proteomics
/ methods
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Sulfonamides
/ pharmacology
bcl-X Protein
/ antagonists & inhibitors
eIF-2 Kinase
/ genetics
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
20
04
2018
revised:
30
08
2018
accepted:
14
01
2019
pubmed:
27
1
2019
medline:
13
3
2020
entrez:
26
1
2019
Statut:
ppublish
Résumé
Most patients with late-stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the proapoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/X
Identifiants
pubmed: 30679390
pii: 1535-7163.MCT-18-0413
doi: 10.1158/1535-7163.MCT-18-0413
pmc: PMC6399746
mid: NIHMS1519283
doi:
Substances chimiques
Aniline Compounds
0
BCL2 protein, human
0
BCL2L1 protein, human
0
Bcl-2-Like Protein 11
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins c-bcl-2
0
Sulfonamides
0
bcl-X Protein
0
EIF2AK3 protein, human
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
navitoclax
XKJ5VVK2WD
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
642-655Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA217685
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA222554
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181543
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA121113
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217842
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA222554
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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