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- Title
Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma.
- Authors
Rebecca, Vito W.; Alicea, Gretchen M.; Paraiso, Kim H. T.; Lawrence, Harshani; Gibney, Geoffrey T.; Smalley, Keiran S. M.
- 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 (p ERK). 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.
- Subjects
MITOGEN-activated protein kinases; NEUROBLASTOMA; MELANOMA; CELL lines; CYCLINS; PATIENTS
- Publication
Pigment Cell & Melanoma Research, 2014, Vol 27, Issue 6, p1154
- ISSN
1755-1471
- Publication type
Article
- DOI
10.1111/pcmr.12303