Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma
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Clemens Krepler1, Min Xiao1, Minu Samanta1, Adina Vultur1, Hsin-Yi Chen1, Patricia Brafford1, Patricia I. Reyes-Uribe1, Molly Halloran1, Thomas Chen1, Xu He1, Denitsa Hristova1, Qin Liu1, Ahmed A. Samatar2, Michael A. Davies3, Katherine L. Nathanson4, Mizuho Fukunaga-Kalabis1, Meenhard Herlyn1 and Jessie Villanueva1
1 The Wistar Institute, Melanoma Research Center, Philadelphia, PA, USA
2 Discovery Oncology Merck Research Laboratories, Boston, MA, USA
3 Melanoma Medical Oncology and Systems Biology University of Texas MD Anderson Cancer Center, Houston, TX, USA
4 Division of Medical Genetics and The Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia PA, USA
Jessie Villanueva, email:
Keywords: melanoma, targeted therapy resistance, ERK, BRAF, Notch
Received: February 29, 2016 Accepted: September 12, 2016 Published: September 16, 2016
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.
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