This is, surprisingly, followed by tumor suppression and decreased metastasis in a mouse model of melanoma . melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed. or among others [17,18,19,20,21], contributes to the pro-survival phenotype of melanoma cells. A negative regulation of pro-apoptotic molecules (e.g., BIM) by oncogenic MAPK signaling has been reported , while anti-apoptotic proteins involved in the regulation of extrinsic and intrinsic apoptotic routes are largely overexpressed in melanoma [23,24]. Other signaling pathways , melanoma-specific transcriptional regulators  and post-transcriptional control  also extensively contribute to the capability of melanoma cells to counteract unfavorable conditions, including exposition to anti-cancer therapies. In addition, microenvironment-mediated regulation of expression of pro-survival molecules, including MCL-1, BCL-XL, and BFL-1 [28,29,30], supports a remarkable adaptive capabilities of melanoma cells. Despite a tremendous advances in the therapeutic options for melanoma patients (Figure 1), inability or limited vulnerability of melanoma cells to induction of apoptosis in response to inhibitors of BRAFmut (BRAFi) and MEK (MEKi) [31,32,33,34,35,36,37,38], and escape from immunotherapy [39,40,41] are the reasons for re-growth of drug-resistant disease. In this respect, research on the mechanisms of the non-apoptotic cell death modalities is attractive in melanoma. Open in a separate window Figure 1 Targeted therapeutics and immunotherapy used in the treatment of melanoma patients. SB-674042 Melanoma cells exert hyperactivation of the RAS/RAF/MEK/ERK signaling pathway that regulates different cellular programs, including survival. Targeted therapeutics (shown in green background) inhibit activity of either mutated BRAF (BRAF*, V600E is the most frequent amino acid substitution) or MEK1/2. BRAFi and MEKi are used as a combinatory treatment SB-674042 regimen. Immunotherapy (shown in yellow background) includes checkpoint inhibitors: antibodies blocking either PD-1 (programmed death-1) or CTLA4 (cytotoxic SB-674042 T-lymphocyte associated protein 4). Both targets for immunotherapy are physiological inhibitors of T cell-mediated immune response. RTK, receptor tyrosine kinase. This review summarizes current knowledge on the role of non-apoptotic cell death signaling pathways in melanoma development and progression, as well as in response of melanoma cells to currently used therapeutics, i.e., BRAFi and MEKi, and immunotherapy. 2. Autophagy 2.1. An Overview of Autophagy and Autophagy-Dependent Cell Death Autophagy is a catabolic process, in which proteins, bulk cytoplasm, and/or organelles are incorporated into double-membrane intracellular vesicles to be recycled within lysosomes. Thus, autophagy maintains cellular homeostasis by the removal of unfolded proteins and damaged organelles [42,43,44,45]. Autophagy can be executed either non-selectively (macroautophagy or autophagy) or in a selective manner to remove specific organelles, e.g., damaged mitochondria (mitophagy)  and peroxisomes (pexophagy) . Autophagy is sustained at a low level in the majority of cells, while its efficiency can be affected by a number of stimuli . Autophagy involves five stages: (1) Initiation, (2) nucleation of the double-membrane vesicles (phagophores, further extended to the autophagosomes), (3) expansion and elongation, (4) closure and fusion of the autophagosomes with the lysosomes, and (5) degradation of intravesicular content (Figure 2) [42,49]. Autophagy-related genes (was sufficient to preclude this process . In addition, exposure to ultraviolet A (UVA) upregulated p62/SQSTM1 and triggered p62-dependent response SB-674042 that involved nuclear factor erythroid 2-related factor 2 (NRF-2 encoded by in a BRAFV600E/. A heterozygous loss of enhanced melanoma metastasis and predicted poor overall patient survival . In addition, miR-23a has been identified as a negative regulator of ATG12 (Figure 2), while ATG12 regulated melanoma cell invasion and migration through AMP-activated protein kinase-RAS homolog family member A (AMPK-RhoA) pathway . Accordingly, expression of miR-23a was decreased in metastatic melanoma CXCR6 cell lines, and miR-23a level was significantly lower in serum of patients with metastatic melanoma . An.