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

被引：52

作者：

Adelmann, Charles H. ^{[1
]}

Ching, Grace ^{[1
]}

Du, Lili ^{[1
]}

Saporito, Rachael C. ^{[1
]}

Bansal, Varun ^{[1
]}

Pence, Lindy J. ^{[1
]}

Liang, Roger ^{[1
]}

Lee, Woojin ^{[1
]}

Tsai, Kenneth Y. ^{[1
,2
,3
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Dermatol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Grad Sch Biomed Sci, Houston, TX 77030 USA

来源：

ONCOTARGET | 2016年 / 7卷 / 21期

关键词：

BRAF; squamous cell carcinoma; small molecule inhibitor; paradoxical ERK; melanoma; RAF INHIBITORS; ADVANCED MELANOMA; KINASE INHIBITOR; MUTANT MELANOMA; MAPK PATHWAY; OPEN-LABEL; VEMURAFENIB; DABRAFENIB; MUTATIONS; MULTICENTER;

D O I：

10.18632/oncotarget.8351

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BRAF inhibitor (BRAFi) therapy is associated with the induction of neoplasia, most commonly cutaneous squamous 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.

引用

页码：30453 / 30460

页数：8

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