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Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma.
- Source :
-
Molecular oncology [Mol Oncol] 2014 May; Vol. 8 (3), pp. 544-54. Date of Electronic Publication: 2014 Jan 15. - Publication Year :
- 2014
-
Abstract
- Acquired resistance to BRAF inhibitors often involves MAPK re-activation, yet the MEK inhibitor trametinib showed minimal clinical activity in melanoma patients that had progressed on BRAF-inhibitor therapy. Selective ERK inhibitors have been proposed as alternative salvage therapies. We show that ERK inhibition is more potent than MEK inhibition at suppressing MAPK activity and inhibiting the proliferation of multiple BRAF inhibitor resistant melanoma cell models. Nevertheless, melanoma cells often failed to undergo apoptosis in response to ERK inhibition, because the relief of ERK-dependent negative feedback activated RAS and PI3K signalling. Consequently, the combination of ERK and PI3K/mTOR inhibition was effective at promoting cell death in all resistant melanoma cell models, and was substantially more potent than the MEK/PI3K/mTOR inhibitor combination. Our data indicate that a broader targeting strategy concurrently inhibiting ERK, rather than MEK, and PI3K/mTOR may circumvent BRAF inhibitor resistance, and should be considered during the clinical development of ERK inhibitors.<br /> (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Apoptosis drug effects
Cell Line, Tumor
Humans
Melanoma metabolism
Mitogen-Activated Protein Kinase Kinases metabolism
Mitogen-Activated Protein Kinases metabolism
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins B-raf metabolism
Signal Transduction drug effects
TOR Serine-Threonine Kinases antagonists & inhibitors
TOR Serine-Threonine Kinases metabolism
Tumor Cells, Cultured
Drug Resistance, Neoplasm
Melanoma drug therapy
Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinases antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins B-raf antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 24476679
- Full Text :
- https://doi.org/10.1016/j.molonc.2014.01.003