title: HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors.
abstract: The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720-30. ©2016 AACR.
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Anna
authors.initials: A
authors.lastname: Budina-Kolomets
authors.affiliation: Program in Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Webster
authors.affiliation: Department of Genetics, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Julia I-Ju
authors.initials: JI
authors.lastname: Leu
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Matthew
authors.initials: M
authors.lastname: Jennis
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Guerrini
authors.affiliation: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Department of Medicine, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Surgery, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Karakousis
authors.affiliation: Department of Medicine, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Lynn
authors.initials: L
authors.lastname: Schuchter
authors.affiliation: Department of Medicine, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Yin
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Pathology and Laboratory Medicine, and Abramson Cancer Center, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Genetics, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Donna L
authors.initials: DL
authors.lastname: George
authors.affiliation: Program in Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
authors.affiliation: Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania. mmurphy@wistar.org.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology*; D046888:Tissue Array Analysis; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf