Efficient Suppression of NRAS-Driven Melanoma by Co-Inhibition of ERK1/2 and ERK5 MAPK Pathways.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
/ drug effects
Female
GTP Phosphohydrolases
/ genetics
Humans
MAP Kinase Signaling System
/ drug effects
Melanoma
/ drug therapy
Membrane Proteins
/ genetics
Mice
Mitogen-Activated Protein Kinase 1
/ antagonists & inhibitors
Mitogen-Activated Protein Kinase 3
/ antagonists & inhibitors
Mitogen-Activated Protein Kinase 7
/ antagonists & inhibitors
Molecular Targeted Therapy
/ methods
Mutation
Protein Kinase Inhibitors
/ pharmacology
Skin
/ pathology
Skin Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Journal
The Journal of investigative dermatology
ISSN: 1523-1747
Titre abrégé: J Invest Dermatol
Pays: United States
ID NLM: 0426720
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
25
10
2019
revised:
24
02
2020
accepted:
18
03
2020
pubmed:
8
5
2020
medline:
2
4
2021
entrez:
8
5
2020
Statut:
ppublish
Résumé
Cutaneous melanoma is a highly malignant tumor typically driven by somatic mutation in the oncogenes BRAF or NRAS, leading to uncontrolled activation of the MEK/ERK MAPK pathway. Despite the availability of immunotherapy, MAPK pathway‒targeting regimens are still a valuable treatment option for BRAF-mutant melanoma. Unfortunately, patients with NRAS mutation do not benefit from such therapies owing to the lack of targetable BRAF mutations and a high degree of intrinsic and acquired resistance toward MEK inhibition. Here, we demonstrate that concomitant inhibition of ERK5 removes this constraint and effectively sensitizes NRAS-mutant melanoma cells for MAPK pathway‒targeting therapy. Using approved MEK inhibitors or a pharmacologic ERK inhibitor, we demonstrate that MAPK inhibition triggers a delayed activation of ERK5 through a PDGFR inhibitor-sensitive pathway in NRAS-mutant melanoma cells, resulting in sustained proliferation and survival. ERK5 phosphorylation also occurred naturally in NRAS-mutant melanoma cells and correlated with nuclear localization of its stem cell-associated effector KLF2. Importantly, MEK/ERK5 co-inhibition prevented long-term growth of human NRAS-mutant melanoma cells in vitro and effectively repressed tumor progression in a xenotransplant mouse model. Our findings suggest MEK/ERK5 cotargeting as a potential treatment option for NRAS-mutant melanoma, which currently is not amenable for targeted therapies.
Identifiants
pubmed: 32376279
pii: S0022-202X(20)31407-X
doi: 10.1016/j.jid.2020.03.972
pii:
doi:
Substances chimiques
Membrane Proteins
0
Protein Kinase Inhibitors
0
MAPK1 protein, human
EC 2.7.11.24
MAPK3 protein, human
EC 2.7.11.24
MAPK7 protein, human
EC 2.7.11.24
Mitogen-Activated Protein Kinase 1
EC 2.7.11.24
Mitogen-Activated Protein Kinase 3
EC 2.7.11.24
Mitogen-Activated Protein Kinase 7
EC 2.7.11.24
GTP Phosphohydrolases
EC 3.6.1.-
NRAS protein, human
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2455-2465.e10Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.