Activation of Receptor Tyrosine Kinases Mediates Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Enzyme Activation
Female
Hepatocyte Growth Factor
/ metabolism
Humans
MAP Kinase Signaling System
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Recurrence, Local
/ drug therapy
Nerve Sheath Neoplasms
/ drug therapy
Neurofibromatosis 1
/ complications
Neurofibromin 1
/ deficiency
Protein Kinase Inhibitors
/ therapeutic use
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ antagonists & inhibitors
Proteomics
Proto-Oncogene Proteins c-met
/ antagonists & inhibitors
Proto-Oncogene Proteins c-raf
/ metabolism
Pyridones
/ pharmacology
Pyrimidinones
/ pharmacology
Random Allocation
Receptor Protein-Tyrosine Kinases
/ metabolism
Receptor, Platelet-Derived Growth Factor beta
/ metabolism
Signal Transduction
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Up-Regulation
ras Proteins
/ antagonists & inhibitors
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
received:
10
06
2020
revised:
08
10
2020
accepted:
12
11
2020
pubmed:
19
11
2020
medline:
30
4
2021
entrez:
18
11
2020
Statut:
ppublish
Résumé
Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of malignant peripheral nerve sheath tumors (MPNST). A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an
Identifiants
pubmed: 33203698
pii: 0008-5472.CAN-20-1992
doi: 10.1158/0008-5472.CAN-20-1992
pmc: PMC7854512
mid: NIHMS1648500
doi:
Substances chimiques
Antineoplastic Agents
0
HGF protein, human
0
NF1 protein, human
0
Neurofibromin 1
0
Protein Kinase Inhibitors
0
Pyridones
0
Pyrimidinones
0
trametinib
33E86K87QN
Hepatocyte Growth Factor
67256-21-7
MTOR protein, human
EC 2.7.1.1
MET protein, human
EC 2.7.10.1
Proto-Oncogene Proteins c-met
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Receptor, Platelet-Derived Growth Factor beta
EC 2.7.10.1
Proto-Oncogene Proteins c-raf
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
PTPN11 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
ras Proteins
EC 3.6.5.2
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
747-762Subventions
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA196519
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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