FIGURE 3.

Adaptive resistance to ERK1/2 pathway inhibition through feedback relief, de-repression of RTKs and activation of ERK5. Activation of ERK1/2 cascade is controlled by homeostatic negative feedback loops operating at various levels including ERK1/2-dependent phosphorylation and inhibition of RAF and RTKs. When ERK1/2 signalling is inhibited by RAFi, MEK1/2i or ERK1/2i these inhibitory feedback loops are lost, resulting in reactivation of the pathway; this is manifest as rapid pathway “rebound” after initial pathway inhibition. Many of these same RTKs are also able to activate the ERK5 pathway, consequently loss of ERK1/2 activity can result in activation of the ERK5 pathway. This is seen in: KRAS-mutant PDAC, where inhibition of ERK1/2 results in activation of EGFR and SRC-dependent activation of ERK5; BRAF-mutant melanoma where inhibition of ERK1/2 results in activation of IGF-1R and thence ERK5 and in NRAS-mutant melanoma where inhibition of MEK1/2 results in activation of PDGFRβ and thence ERK5. In such cases, co-administration of ERK1/2 pathway therapeutics and ERK5i may be indicated.