Thursday, February 9, 2012
Figure 1. BRAF inhibition leads to EGFR-mediated pathway
activation. Two groups
suggest epidermal growth factor receptor
activation evades BRAF inhibition. Each
group has its own idea about the mechanism by which EGFR potentially mediates
the pathway activation that leads to renewed cell growth.
al. think that in
BRAF(V600E)-mutant cancers, normal EGFR signaling results in activation of both
the phosphoinositide 3-kinase
(PI3K)-protein kinase B (PKB; PKBA; AKT; AKT1) pathway and the Ras-Raf-MEK-MAPK (ERK)
pathway. Cell division
cycle 25C (CDC25C;
binds to and deactivates EGFR (I). The group postulates that BRAF inhibition leads to
decreased CDC25C activity and increased EGFR activation (EGFR*). EGFR* then
results in greater activation of the PI3K-AKT pathway (bold arrows in II).
Corcoran et al. think that in BRAF(V600E)-mutant cancers,
EGFR* does not activate Ras, due to an ERK-dependent negative feedback loop-possibly
via sprouty (SPRY)
The group postulates that BRAF inhibition leads to feedback activation of Ras
by EGFR, allowing EGFR to reactivate the Ras-Raf-MEK-ERK pathway (bold arrows
either of the proposed EGFR-mediated mechanisms, EGFR inhibitors would
potentially block pathway activation and subsequent renewed cell growth.