Reactivation Of The AKT Survival Pathway By ERK1/2
Why inhibition of both pathways is important
In the study by Toulany et al., it was demonstrated for the first time that long term treatment with inhibitors of PI3K (as it is performed clinically) results in a reactivation of the major survival component Akt through a so far unknown regulatory loop via ERK1/2. This reactivation of Akt limits quite efficiently the response of the tested tumor cell lines presenting constitutively active K-Ras activity (both through K-RAS mutation or over-expression of K-RAS wildtype) to antagonistic strategies directed against PI3K. Thus, the described ERK1/2 dependency of reactivation of Akt gives new insights into the underlying mechanisms of resistance accompanying EGFR and PI3K antagonizing strategies. Moreover and clinically perhaps even more importantly, these findings provide specific hints how the combination of MEK-ERK1/2 and PI3K inhibitors can efficiently be used to overcome therapy resistance of tumors presenting constitutively high K-Ras activity.
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