SHP2 phosphatase as a novel therapeutic target for melanoma treatment.

Ruo-Yu Zhang,Zhi-Hong Yu,Jinmin Miao,Lan Chen,Jingwu Xie,Yunpeng Bai,Sheng Zhang,Zhong-Yin Zhang,Lifan Zeng

doi:10.18632/oncotarget.12074

Abstract

Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.

Highlights

Melanoma is a malignant tumor of melanocytes and ranks among the most common cancers in the United States
These clinical data suggest that SHP2 may play a role in melanoma onset and progression, and targeting SHP2 may be beneficial for melanoma treatment
Since c-Met is a receptor tyrosine kinase involved in melanoma [7, 8, 10], we further evaluated whether SHP2 could affect aforementioned signals upon HGF stimulation (Figure 3C)

Summary

Introduction

New treatments for melanoma have been developed over the past few years, including a number of molecular targeted and immunotherapeutic approaches. These targeted approaches are usually effective only in a subset of patients and the emergence of drug resistance further reduces durable responses [1]. The extracellular signal-regulated kinase (ERK1/2) pathway, which controls key cellular processes such as proliferation, invasion, and survival, is frequently activated in human cancers including melanoma. Constitutive activation of PI3KAKT pathway facilitates melanoma progression, possibly by enhanced cell survival [5]. Several growth factor receptors acting upstream of ERK1/2 and PI3K-AKT cascades are implicated in melanoma. Melanoma arising from mucosal, acral, and chronically sun-damaged sites commonly has amplifications or activating mutations in KIT [11]

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Conclusion