BRAF inhibition promotes ER stress-mediated cell death in uveal melanoma

Yinu Zhao, Yue Wang, Li Zhang, Weibin Wang, Thomas Fahey,  Ke Yao

Abstract:

Melanoma with a BRAF mutation is more common to develop into a fatal disease. BRAF mutation inhibitor-induced autophagy affects the drug efficacy in many cancer types. The role of autophagy during BRAF inhibition in uveal melanoma (UM) remains unclear. In this study, we examined the autophagic flux and compared the number of autophagic vacuoles during the BRAF inhibition in UM. The PKR-like endoplasmic reticulum (ER) kinase (PERK) arm was studied to test whether the ER stress was involved. The effects of downregulation of ER stress by targeting the PERK arm (pharmacologically and genetically) were also assessed. We found a dose-dependent increase of autophagic flux in OCM1A cells during the BRAF inhibition. This phenomenon was further verified by an enhanced number of GFP-LC3 puncta and was finally confirmed by raised autophagic index examined by transmission electron microscopy. Pathway analysis revealed that the vemurafenib (the BRAF inhibitor)-induced autophagy was independent of the MAPK signaling pathway. Instead, it was possibly regulated via the enhanced ER stress response. We further found that the inhibition of ER stress response rescued cell death. Therefore, our results suggest BRAF inhibition promotes ER stress response-induced autophagy in UM. Targeting ER stress response can partially revert autophagy and rescue cell death, which may impair the anti-tumor effect of BRAF inhibitor in UM.