Abstract
The MEK inhibitor MEK162 is the first targeted therapy agent with clinical activity in patients whose melanomas harbor NRAS mutations; however, median PFS is 3.7 months, suggesting the rapid onset of resistance in the majority of patients. Here, we show that treatment of NRAS-mutant melanoma cell lines with the MEK inhibitors AZD6244 or trametinib resulted in a rebound activation of phospho-ERK (pERK). Functionally, the recovery of signaling was associated with the maintenance of cyclin-D1 expression and therapeutic escape. The combination of a MEK inhibitor with an ERK inhibitor suppressed the recovery of cyclin-D1 expression and was associated with a significant enhancement of apoptosis and the abrogation of clonal outgrowth. The MEK/ERK combination strategy induced greater levels of apoptosis compared with dual MEK/CDK4 or MEK/PI3K inhibition across a panel of cell lines. These data provide the rationale for further investigation of vertically co-targeting the MAPK pathway as a potential treatment option for NRAS-mutant melanoma patients.
Original language | English (US) |
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Pages (from-to) | 1154-1158 |
Number of pages | 5 |
Journal | Pigment Cell and Melanoma Research |
Volume | 27 |
Issue number | 6 |
DOIs | |
State | Published - Nov 1 2014 |
Externally published | Yes |
Keywords
- AZD6244
- ERK
- Melanoma
- NRAS
- Trametinib
ASJC Scopus subject areas
- Oncology
- General Biochemistry, Genetics and Molecular Biology
- Dermatology