Figure 3.

Adaptive response-mediated resistance to BRAF inhibitors in melanoma. (A) Negative feedback regulation of activated ERK on EGFR, RAF, and MEK, resulting in the downregulation of MAPK signalling. Figure 3 highlights the relief of these downstream kinase-dependent negative feedback loops, following MAPK inhibition. (B) Transcriptionally-mediated feedback loops regulating resistance to BRAF inhibitors. These feedback loops result in re-activation of the MAPK pathway (DUSP, USP28, FOXD3/ERBB3. TGFB/EGFR), parallel activation of PI3K pathway (FOXD3/ERBB3, TGFB/EGFR), increase oxidative phosphorylation (PGC1α, lncRNA SAMMSON, MITF), and autophagy related genes mediated by TFEB. RAF, RAF proto oncogene; MEK/MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinase. SHC, SHC adaptor protein 1; GRB2, growth factor receptor bound protein 2; SOS, son of sevenless; RAS, RAS proto-oncogene; USP28, Ubiquitin specific protease 28; KSR, Kinase Suppressor of RAS; EGFR, epidermal growth factor receptor; ERBB3, Erb-B2 receptor tyrosine kinase 3; PI3K, Phosphoinositide 3-kinase; AKT, AKT serine/threonine kinase; MITF, melanocyte inducing transcription factor; SOX10, SRY-box 10; TGFβ, transforming growth factor β, TFEB, transcription factor EB; FOXD3, forkhead box D3; DUSP, dual specificity phosphatase; PGC1α, Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, TF, transcription factors.