Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor Academic Article uri icon

Overview

MeSH Major

  • Benzimidazoles
  • Carbamates
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Signaling System
  • Protein Kinase Inhibitors
  • T-Lymphocyte Subsets
  • raf Kinases

abstract

  • RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.

publication date

  • January 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3883307

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-13-0160

PubMed ID

  • 24416731

Additional Document Info

start page

  • 70

end page

  • 9

volume

  • 2

number

  • 1