fig3

Figure 3. (A) Schematic representation of cellular targets of HDACi and targeted BRAF mutant therapy concepts of relevance for cell death mechanisms. Classification of BRAF mutations is depicted according to Ras dependency. Class I BRAFi like vemurafenib, a reversible ATP competitive inhibitor of the BRAF serine-threonine kinase, act as a repressor of the activated MAPK signaling pathway. Class II and Class III inhibitors like trametinib are downstream inhibitors of the MAPK pathway, the MEK or inhibitors of RTK. HDAC inhibitors targeting cancer cell-related pathways are described as a promising approach to overcoming BRAF mutation-induced therapy resistance. The cellular HDAC-related targets are located either in the cytosol or the nucleus. For example, the inhibition of the cytosolic HDAC6/10 by the pan HDAC inhibitor givinostat leads to activation and acetylation of p53 together with disruption of Hsp90 chaperone function, leading to pronounced anticancer effects such as apoptosis and cell cycle arrest; (B) Synergistic effects of BRAF and HDAC inhibitors on cell death mechanisms. HDACi: Histone deacetylase inhibitors; BRAFi: BRAF inhibitors; BRAF: B-Raf, B-rapidly accelerated fibrosarcoma; MEK: MAPK/ERK kinase; RTK: receptor tyrosine kinases; ac: acetyl group; MAPK: mitogen-activated protein kinase.