Figure 2.

Reactivation of the mitogen-activated protein kinase (MAPK) pathway resulting from the relief of negative feedback loops. (a) In melanoma cells containing the BRAF-V600E mutation, MAPK signaling is highly active and leads to enhanced expression of several genes promoting cell proliferation and survival, but also of other genes involved in negative feedback loops, including DUSP and SPRY. (b,c) Pharmacological inhibition of the MAPK pathway with the BRAF inhibitor vemurafenib provokes downregulation of DUSP and SPRY (b), thus relieving the negative feedback loop (c). In these conditions, some level of signaling can be reactivated independently of the BRAF mutation. (d) A similar adaptive response to BRAF inhibition relies on the overexpression of PDGFR, resulting in an upstream activation of the pathway that bypasses mutant BRAF.