2. Academic Validation
  3. HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors

HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors

  • Cancer Res. 2016 May 1;76(9):2720-30. doi: 10.1158/0008-5472.CAN-15-2137.
Anna Budina-Kolomets 1,  Marie R Webster 2,  Julia I-Ju Leu 3,  Matthew Jennis 1,  Clemens Krepler 1,  Anastasia Guerrini 1,  Andrew V Kossenkov 4,  Wei Xu 5,  Giorgos Karakousis 6,  Lynn Schuchter 5,  Ravi K Amaravadi 5,  Hong Wu 7,  Xiangfan Yin 1,  Qin Liu 1,  Yiling Lu 8,  Gordon B Mills 8,  Xiaowei Xu 9,  Donna L George 3,  Ashani T Weeraratna 2,  Maureen E Murphy 10
Affiliations

Affiliations

  • 1 Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
  • 2 Program in Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
  • 3 Department of Genetics, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
  • 4 Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania.
  • 5 Department of Medicine, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
  • 6 Department of Surgery, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
  • 7 Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • 8 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 9 Department of Pathology and Laboratory Medicine, and Abramson Cancer Center, The Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania.
  • 10 Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania. mmurphy@wistar.org.
PMID: 26984758 DOI: 10.1158/0008-5472.CAN-15-2137
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.

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