TY - JOUR
T1 - HSP70 inhibition limits FAK-dependent invasion and enhances the response to melanoma treatment with BRAF inhibitors
AU - Budina-Kolomets, Anna
AU - Webster, Marie R.
AU - Leu, Julia I.Ju
AU - Jennis, Matthew
AU - Krepler, Clemens
AU - Guerrini, Anastasia
AU - Kossenkov, Andrew V.
AU - Xu, Wei
AU - Karakousis, Giorgos
AU - Schuchter, Lynn
AU - Amaravadi, Ravi K.
AU - Wu, Hong
AU - Yin, Xiangfan
AU - Liu, Qin
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Xu, Xiaowei
AU - George, Donna L.
AU - Weeraratna, Ashani T.
AU - Murphy, Maureen E.
N1 - Funding Information:
This work was supported by NIH R01 139319 (M.E. Murphy), P01 114046-07 (M.E. Murphy, D.L. George, and A.T. Weeraratna), and R01 CA174746-01 (A.T. Weeraratna), as well as T32 CA009171-36 (M.R. Webster). The IHC and IF studies were supported by the Molecular Pathology & Imaging Core, Perelman School of Medicine, University of Pennsylvania (NIH P30 DK050306). The RPPA analysis was funded by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to Meenhard Herlyn (The Wistar Institute). Support for Core Facilities utilized in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-2137
DO - 10.1158/0008-5472.CAN-15-2137
M3 - Article
C2 - 26984758
AN - SCOPUS:84969651143
SN - 0008-5472
VL - 76
SP - 2720
EP - 2730
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -