title: SHP2 phosphatase as a novel therapeutic target for melanoma treatment.
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Lifan
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jinmin
authors.initials: J
authors.lastname: Miao
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jingwu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.|Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: SHP2; SHP2 inhibitor; drug discovery; melanoma; protein tyrosine phosphatase