ArticleCancer immunology research2014
Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor.
Article in Cancer immunology research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
66 citing papers in PubMed, 1 synthesis or guideline pooled it, 119 citations in OpenAlex.
- Prognostic factors and outcome measures after BRAF-directed targeted therapy of unresectable metastatic BRAFInvestigational new drugs · 2026Pooled it
- Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFCancer cell · 2025Trial
- Trial
- Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial.Nature medicine · 2024Trial
- Article
- A Phase 1/1B Trial of Pembrolizumab and Trametinib in Advanced NSCLC Enriched for KRAS Mutations.JTO clinical and research reports · 2025Article
- Tumor eradication by triplet therapy with BRAF inhibitor, TLR 7 agonist, and PD-1 antibody for BRAF-mutated melanoma.Cancer science · 2024Article
- Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function.Life science alliance · 2024Article
- Immunotherapy combination approaches: mechanisms, biomarkers and clinical observations.Nature reviews. Immunology · 2024Review
- Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.Oncotarget · 2024Article
- TIM-3, LAG-3, or 2B4 gene disruptions increase the anti-tumor response of engineered T cells.Frontiers in immunology · 2024Article
- Review
- Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?Cancer metastasis reviews · 2023Review
- PD-1 or PD-L1 Blockade Adds Little to Combination of BRAF and MEK Inhibition in the Treatment of BRAF V600-Mutated Melanoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022Article
- Genomic and Transcriptomic Correlates of Thyroid Carcinoma Evolution after BRAF Inhibitor Therapy.Molecular cancer research : MCR · 2022Article
- Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma.Frontiers in oncology · 2022Article
- Intermittent MEK inhibition for the treatment of metastatic uveal melanoma.Frontiers in oncology · 2022Article
- Polyglutamate-based nanoconjugates for image-guided surgery and post-operative melanoma metastases prevention.Theranostics · 2022Article
- Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.Frontiers in oncology · 2022Review
- Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
16 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.