HSP70 inhibition limits FAK-dependent invasion and enhances the response to melanoma treatment with BRAF inhibitors

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

    Research output: Contribution to journalArticle

    14 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)2720-2730
    Number of pages11
    JournalCancer Research
    Volume76
    Issue number9
    DOIs
    StatePublished - May 1 2016

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Budina-Kolomets, A., Webster, M. R., Leu, J. I. J., Jennis, M., Krepler, C., Guerrini, A., Kossenkov, A. V., Xu, W., Karakousis, G., Schuchter, L., Amaravadi, R. K., Wu, H., Yin, X., Liu, Q., Lu, Y., Mills, G. B., Xu, X., George, D. L., Weeraratna, A. T., & Murphy, M. E. (2016). HSP70 inhibition limits FAK-dependent invasion and enhances the response to melanoma treatment with BRAF inhibitors. Cancer Research, 76(9), 2720-2730. https://doi.org/10.1158/0008-5472.CAN-15-2137