Figure 1. BRAF inhibition leads to EGFR-mediated pathway activation. Two groups suggest epidermal growth factor receptor (EGFR)-mediated pathway 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.

Prahallad et 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; CDC25) 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) proteins (III). 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 in IV).

For either of the proposed EGFR-mediated mechanisms, EGFR inhibitors would potentially block pathway activation and subsequent renewed cell growth.