Open AccessTargeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
Author(s) -
Clemens Krepler,
Min Xiao,
Minu Samanta,
Adina Vultur,
Hsin Yi Chen,
Patricia Brafford,
Patricia Reyes-Uribe,
Molly B. Halloran,
Thomas Chen,
Xijing He,
Denitsa M. Hristova,
Qin Liu,
Ahmed A. Samatar,
Michael A. Davies,
Katherine L. Nathanson,
Mizuho Fukunaga-Kalabis,
Meenhard Herlyn,
Jessie Villanueva
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.12078
Subject(s) - mapk/erk pathway , melanoma , pten , cancer research , medicine , notch signaling pathway , mek inhibitor , pi3k/akt/mtor pathway , kinase , signal transduction , biology , receptor , microbiology and biotechnology
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.