Targeted BRAF inhibition impacts survival in melanoma patients with high levels of Wnt/β-catenin signaling.

Andy J Chien,Richard A Scolyer,Randall T Moon,Richard F Kefford,Georgina V Long,Rima M Kulikauskas,Lauren E Haydu,Travis L Biechele,Helen Rizos

doi:10.1371/journal.pone.0094748

Abstract

Unprecedented clinical responses have been reported in advanced stage metastatic melanoma patients treated with targeted inhibitors of constitutively activated mutant BRAF, which is present in approximately half of all melanomas. We and others have previously observed an association of elevated nuclear β-catenin with improved survival in molecularly-unselected melanoma patients. This study sought to determine whether levels of Wnt/β-catenin signaling in melanoma tumors prior to treatment might predict patient responses to BRAF inhibitors (BRAFi). We performed automated quantification of β-catenin immunohistochemical expression in pretreatment BRAF-mutant tumors from 32 BRAFi-treated melanoma patients. Unexpectedly, patients with higher nuclear β-catenin in their tumors did not exhibit the survival advantage previously observed in molecularly-unselected melanoma patients who did not receive BRAFi. In cultured melanoma cells treated with long-term BRAFi, activation of Wnt/β-catenin signaling is markedly inhibited, coinciding with a loss of the enhancement of BRAFi-induced apoptosis by WNT3A observed in BRAFi-naïve cells. Together, these observations suggest that long-term treatment with BRAFi can impact the interaction between BRAF/MAPK and Wnt/β-catenin signaling to affect patient outcomes. Studies with larger patient cohorts are required to determine whether nuclear β-catenin expression correlates with clinical responses to BRAFi and to specific mechanisms of acquired resistance to BRAFi. Understanding these pathway interactions will be necessary to facilitate efforts to individualize therapies for melanoma patients.

Highlights

The incidence and mortality associated with melanoma has risen steadily since the 1970s in the USA, Europe and Australia [1], and the five-year survival rate of 5–15% for patients with advanced stage metastatic disease has remained stagnant over that time
This study unexpectedly found that increased nuclear b-catenin in biopsies taken prior to commencing BRAF inhibitors (BRAFi) therapy is associated with decreased survival in patients treated with BRAFi
Decreased Wnt/b-catenin signaling was seen in patient tumors after progression on BRAFi, which may result from negative regulation of Wnt/b-catenin signaling by ERK1/2 reactivation following the acquisition of BRAFi resistance

Summary

Introduction

The incidence and mortality associated with melanoma has risen steadily since the 1970s in the USA, Europe and Australia [1], and the five-year survival rate of 5–15% for patients with advanced stage metastatic disease has remained stagnant over that time. Mutation-targeted BRAF inhibitors (BRAFi) such as vemurafenib (PLX4032) and dabrafenib (GSK2118436) represent a landmark development in the treatment of advanced stage BRAFV600E/K-mutant metastatic melanoma, with objective response rates of approximately 50%, and in phase III trials, a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with dacarbazine chemotherapy [10,11,12,13,14]. Almost all patients with tumors harboring activating BRAF mutations in these trials exhibit some degree of tumor reduction, even if they do not meet the criteria for an objective clinical response. What types of molecular and cellular determinants underlie the heterogeneity in therapeutic responses observed across patients with tumors harboring activating BRAF mutations and how can these determinants be utilized to predict clinical

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Conclusion