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Ref Type Journal Article
PMID (26984758)
Authors Budina-Kolomets A, Webster MR, Leu JI, Jennis M, Krepler C, Guerrini A, Kossenkov AV, Xu W, Karakousis G, Schuchter L, Amaravadi RK, Wu H, Yin X, Liu Q, Lu Y, Mills GB, Xu X, George DL, Weeraratna AT, Murphy ME
Title HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 76 9 2016 May 01 2720-30 Cancer Res
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PET-16 PET-16 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PET-16 NSC62727|NSC-62727 PET-16 (NSC62727) binds to the substrate-binding domain of Hsp70 and inhibits Hsp70 functions, resulting in decreased tumor metastasis and growth (PMID: 26984758, PMID: 27447295).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF mutant melanoma sensitive PET-16 + Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, PET-16 and Zelboraf (vemurafenib) synergistically inhibited growth of melanoma cell lines in culture, resulted in enhanced tumor growth inhibition in cell ine xenograft models (PMID: 26984758). 26984758