Oncogenic BRAF, endoplasmic reticulum stress, and autophagy: Crosstalk and therapeutic targets in cutaneous melanoma

BRAF is a member of the RAF family of serine/threonine-specific protein kinases. Oncogenic BRAF, in particular, BRAF V600E, can disturb the normal protein folding machinery in the endoplasmic reticulum (ER) leading to accumulation of unfolded/misfolded proteins in the ER lumen, a condition known as endoplasmic reticulum (ER) stress. To alleviate such conditions, ER-stressed cells have developed a highly robust and adaptable signaling network known as unfolded protein response (UPR). UPR is ordinarily a cytoprotective response and usually operates through the induction of autophagy, an intracellular lysosomal degradation pathway that directs damaged proteins, protein aggregates, and damaged organelles for bulk degradation and recycling. Both ER stress and autophagy are involved in the progression and chemoresistance of melanoma. Melanoma, which arises as a result of malignant transformation of melanocytes, exhibits exceptionally high therapeutic resistance. Many mechanisms of therapeutic resistance have been identified in individual melanoma patients and in preclinical BRAF-driven melanoma models. Recently, it has been recognized that oncogenic BRAF interacts with GRP78 and removes its inhibitory influence on the three fundamental ER stress sensors of UPR, PERK, IRE1α, and ATF6. Dissociation of GRP78 from these ER stress sensors prompts UPR that subsequently activates cytoprotective autophagy. Thus, pharmacological inhibition of BRAF-induced ER stress-mediated autophagy can potentially resensitize BRAF mutant melanoma tumors to apoptosis. However, the underlying molecular mechanism of how oncogenic BRAF elevates the basal level of ER stress-mediated autophagy in melanoma tumors is not well characterized. A better understanding of the crosstalk between oncogenic BRAF, ER stress and autophagy may provide a rationale for improving existing cancer therapies and identify novel targets for therapeutic intervention of melanoma.