HSP70 inhibition limits FAK-dependent invasion and enhances the response to melanoma treatment with BRAF inhibitors
Menée in vitro et in vivo sur des modèles de mélanome, cette étude met en évidence des mécanismes suggérant l'intérêt thérapeutique de combiner un inhibiteur de HSP70 avec un inhibiteur de BRAF
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 reduces 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.