Comparative profiles of BRAF inhibitors: the paradox index as a predictor of clinical toxicity

BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2016-05, Vol.7 (21), p.30453-30460
Main Authors: Adelmann, Charles H, Ching, Grace, Du, Lili, Saporito, Rachael C, Bansal, Varun, Pence, Lindy J, Liang, Roger, Lee, Woojin, Tsai, Kenneth Y
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Carbamates - adverse effects
Carcinoma, Squamous Cell - chemically induced
Cell Line
Cell Line, Tumor
Enzyme Activation - drug effects
Heterocyclic Compounds, 2-Ring - adverse effects
Humans
Imidazoles - adverse effects
Indoles - adverse effects
MAP Kinase Signaling System - drug effects
Mitogen-Activated Protein Kinase 1 - metabolism
Oximes - adverse effects
Protein Kinase Inhibitors - adverse effects
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Research Paper
Skin Neoplasms - chemically induced
Sulfonamides - adverse effects
Vemurafenib
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous cell carcinoma (cuSCC). This toxicity is explained in part by "paradoxical ERK activation," or the hyperactivation of ERK signaling by BRAFi in BRAF wild-type cells. However, the rate of cuSCC induction varies widely among BRAFi. To explore this mechanistically, we profiled paradoxical ERK activation by vemurafenib, dabrafenib, encorafenib (LGX818), and PLX8394, demonstrating that vemurafenib induces ERK activation the greatest, while dabrafenib and encorafenib have higher "paradox indices", defined as the pERK activation EC80 divided by the IC80 against A375, corresponding to wider therapeutic windows for achieving tumor inhibition without paradoxical ERK activation. Our results identify differences in the paradox indices of these compounds as a potential mechanism for the differences in cuSCC induction rates and highlight the utility of using ERK activity as a biomarker for maximizing the clinical utility of BRAFi.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.8351