Mechanism and Consequences of RAF Kinase Activation by Small-molecule Inhibitors

Overview

Journal Br J Cancer

Specialty Oncology

Date 2014 Mar 20

PMID 24642617

Citations 50

Authors

M Holderfield

T E Nagel

D D Stuart

Affiliations

Soon will be listed here.

Abstract

Despite the clinical success of RAF inhibitors in BRAF-mutated melanomas, attempts to target RAF kinases in the context of RAS-driven or otherwise RAF wild-type tumours have not only been ineffective, but RAF inhibitors appear to aggravate tumorigenesis in these settings. Subsequent preclinical investigation has revealed several regulatory mechanisms, feedback pathways and unexpected enzymatic quirks in the MAPK pathway, which may explain this paradox. In this review, we cover the various proposed molecular mechanisms for the RAF paradox, the clinical consequences and strategies to overcome it.

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