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Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma.
- Source :
-
Oncotarget [Oncotarget] 2016 Nov 01; Vol. 7 (44), pp. 71211-71222. - Publication Year :
- 2016
-
Abstract
- The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy.
- Subjects :
- Amyloid Precursor Protein Secretases antagonists & inhibitors
Animals
Cell Line, Tumor
Humans
Melanoma genetics
Melanoma pathology
Mice
PTEN Phosphohydrolase physiology
Phosphatidylinositol 3-Kinases physiology
Receptors, Notch physiology
Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors
Indazoles therapeutic use
Melanoma drug therapy
Piperazines therapeutic use
Protein Kinase Inhibitors therapeutic use
Proto-Oncogene Proteins B-raf genetics
Receptors, Notch antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 44
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27655717
- Full Text :
- https://doi.org/10.18632/oncotarget.12078