The eIF4F translation initiation complex plays a critical role
in melanoma resistance to BRAF and MEK inhibitors. Its function
in treatment-naïve cells has been less well studied. We find
that in these cells, eIF4F inhibition raises the activity of
both signaling pathways examined in this thesis – ERK and AMPK
signaling. One of them is already driven by an activating
oncogenic mutation, yet its output rises further when
translation is blocked.
In melanoma cells harboring BRAF or NRAS mutations, eIF4F keeps
ERK signaling intensity within the range the cells tolerate. It
does so through DUSP6/MKP-3, a short-lived phosphatase which
requires continuous eIF4F-dependent production. When this
production stops, DUSP6 is rapidly depleted, the negative
feedback on ERK is disrupted, and ERK activity rises while MEK
phosphorylation remains unchanged. Quantitative reporter
analyses further reveal a high spare signaling capacity in the
ERK pathway, indicating that eIF4F-dependent feedback keeps a
substantial portion of ERK molecules inactive.
eIF4F also restrains AMPK, in cells in which strong ERK
signaling and AMPK activity are considered incompatible. This
control bypasses the canonical upstream kinase LKB1 and
operates instead through the phosphatase PP2A and its adaptor
UHRF1, both of which likewise depend on eIF4F. Crucially, PP2A
also acts on ERK, so a single phosphatase links the two
pathways, and its loss releases them simultaneously.
eIF4F is known as a driver of resistance to targeted therapy.
In our results, it emerges as the regulator of oncogenic
signaling intensity in melanoma cells that are not yet
resistant, sustaining the phosphatases that keep both pathways
within the optimal range that cells tolerate. Removing those
brakes pushes the cells out of the MAPK fitness zone their
growth depends on and identifies translational control as a
potential therapeutic target even before resistance develops.