Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor Journal Article

Authors: Callahan, M. K.; Masters, G.; Pratilas, C. A.; Ariyan, C.; Katz, J.; Kitano, S.; Russell, V.; Gordon, R. A.; Vyas, S.; Yuan, J. D.; Gupta, A.; Wigginton, J. M.; Rosen, N.; Merghoub, T.; Jure-Kunkel, M.; Wolchok, J. D.
Article Title: Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor
Abstract: RAF inhibitors selectively block extracellular signal-regulated kinase (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 on 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 cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade in vivo potentiates T-cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Finally, this combination demonstrates superior antitumor activity, compared with 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. (C) 2013 AACR.
Keywords: survival; ctla-4; tumor; expression; metastatic melanoma; cancer-patients; antitumor-activity; blockade; vemurafenib; braf inhibition
Journal Title: Cancer Immunology Research
Volume: 2
Issue: 1
ISSN: 2326-6066
Publisher: American Association for Cancer Research  
Date Published: 2014-01-01
Start Page: 70
End Page: 79
Language: English
ACCESSION: WOS:000340030900009
DOI: 10.1158/2326-6066.cir-13-0160
PMCID: PMC3883307
PUBMED: 24416731
Notes: Article -- Source: Wos
Altmetric Score
MSK Authors
  1. Neal Rosen
    366 Rosen
  2. Jedd D Wolchok
    669 Wolchok
  3. Taha Merghoub
    209 Merghoub
  4. Margaret Kathleen Callahan
    103 Callahan
  5. Ruth-Ann Roman
    30 Roman
  6. Charlotte Eielson Ariyan
    78 Ariyan
  7. Jianda Yuan
    100 Yuan
  8. Shigehisa Kitano
    10 Kitano
  9. Shachi Vyas
    3 Vyas