Figure 3. Alterations in ERK dynamics as a result of oncogenic mutations and inhibitors.

(A) In cells with wild type (WT) pathway genes, ERK undergoes fast activation and deactivation in response to optogenetic stimulation of SOS. BRAF G491A mutation leads to slower deactivation time (top). When stimuli are frequent, ERK responses are elongated into sustained activity (bottom), leading to aberrant transcriptional regulation of target genes [23]. (B) Mutations in KRAS drive increased baseline ERK activity. Maximum activity levels upon stimulation remain similar [68,110]. (C) Malignant cells release paracrine signals that stimulate sporadic and pulsatile ERK activity in neighboring wild-type cells [24,68]. (D) Modulation of ERK dynamics by pharmacological inhibitors. In wild-type cells, the pattern of normal pulsatile signaling (typically resulting from paracrine stimuli [55]) can be altered by the addition of various pharmacological inhibitors (dashed vertical line). EGFR inhibition (EGFRi) quickly abrogates ERK activation, but pulsatile signaling re-emerges within several hours [37]. RAF inhibitors (RAFi) can generate low-frequency ERK pulses [126], potentially as a result of paradoxical activation of RAF. Non-EGFR receptor tyrosine kinase inhibitors(RTKi) result in high-frequency pulses of ERK [126]. In cells carrying oncogenic RAS or RAF mutations, baseline ERK signaling is elevated and inhibition of RAF or MEK (RAFi/MEKi) suppresses ERK signaling initially. A rebound of ERK activity occurs in a subpopulation of cells (solid red line) within several hours, while other cells remain sensitive (dashed red line) [109,128]. All curves shown are approximated depictions of experimental data.