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Suppl. Figure 6 from HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors

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posted on 2023-03-31, 00:05 authored by Anna Budina-Kolomets, Marie R. Webster, Julia I-Ju Leu, Matthew Jennis, Clemens Krepler, Anastasia Guerrini, Andrew V. Kossenkov, Wei Xu, Giorgos Karakousis, Lynn Schuchter, Ravi K. Amaravadi, Hong Wu, Xiangfan Yin, Qin Liu, Yiling Lu, Gordon B. Mills, Xiaowei Xu, Donna L. George, Ashani T. Weeraratna, Maureen E. Murphy

Impact of PET-16 on ER stress Melanoma cell lines 1205Lu and WM852 were treated with DMSO or 1 μM PET-16 for 0, 8 and 24 hours.

Funding

NIH

Cancer Center Support

History

ARTICLE 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.