Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma.

Clemens Krepler,Meenhard Herlyn,Min Xiao,Qin Liu,Ahmed A Samatar,Mizuho Fukunaga-Kalabis,Adina Vultur,Patricia Brafford,Michael A Davies,Denitsa Hristova,Xu He,Thomas Chen,Jessie Villanueva,Patricia I Reyes-Uribe,Molly Halloran,Hsin-Yi Chen,Katherine L Nathanson,Minu Samanta

doi:10.18632/oncotarget.12078

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.

Highlights

Melanoma is the most lethal form of skin cancer
ERK has emerged as a promising target for melanoma, for melanomas refractory to BRAF and MEK inhibitors using novel ERK inhibitors such as SCH772984 [8], or its clinical analog MK-8353
Not all BRAF-V600E melanomas respond to these drugs ; we found that the PI3K and Notch pathways were differentially activated in responder vs. non-responder melanomas

Summary

Introduction

Melanoma is the most lethal form of skin cancer. More than 76,000 new cases of melanoma are expected to be diagnosed in the United States this year, with an estimated 9,710 deaths [1]. Even though significant progress has been made treating metastatic melanoma, the 5-year survival rate for patients with distant metastatic disease is ~15%. Effective and durable therapies for melanoma are urgently needed. Important progress has been made in recent years identifying the genetic alterations and signaling pathways deregulated in melanoma [2]. Almost 50% of melanomas harbor activating mutations in the BRAF oncogene, predominantly V600E, leading to constitutive activation of the mitogen activated protein kinase (MAPK) pathway [3]

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