Endoplasmic reticulum stress-mediated pathways to both apoptosis and autophagy: Significance for melanoma treatment

Figure 2 Proposed models for the mechanistic role of endoplasmic reticulum stress in the modulation of the anti-tumor efficiency of vemurafenib, dabrafenib and trametenib in melanoma patients harboring activating neuroblastoma RAS viral (v-ras) oncogene homolog or rapidly accelerated fibrosarcoma murine sarcoma viral (v-raf) oncogene homolog B mutations. The main function of MC1R, TRK on melanoma cell is to transmit extracellular signaling that is essential for the activation of RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways to mediate various cellular functions including melanoma initiation, progression and resistance. Thus, the exposure of melanoma (BRAF^mt and NRAS^mt) cells to either Vemurafenib, Dabrafenib or Trametenib, respectively, results in inhibition of MC1R, cKIT and TRK-mediated activation of RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways. As consequence the inhibition of RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathways results in the execution melanoma cell death via mechanism-mediated by ER stress-dependent pathways including PERK-eIF2α-ATF4-ATF3-CHOP-Bim pathway. NRAS: Neuroblastoma Rat Sarcoma viral (v-ras) oncogene homolog; BRAF: Rapidly Accelerated Fibrosarcoma murine sarcoma viral (v-raf) oncogene homolog B; MC1R: Melanocortin 1 receptor; TRK: CKIT and receptor tyrosine kinase; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; AKT: Protein kinase B.