The kinase inhibitors dabrafenib and trametinib affect isolated immune cell populations

Vella, Laura J.; Andrews, Miles C.; Pasam, Anupama; Woods, Katherine; Behren, Andreas; Cebon, Jonathan

doi:10.4161/21624011.2014.946367

Cited by 13 publications

(13 citation statements)

References 10 publications

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“…These effects cannot be simply modeled in mice. Empirically derived optimal dosing and schedules will be needed in in vivo models and in humans to show that use of kinase inhibition to regulate immunotherapy has therapeutic benefits while sparing immune effector cells of the detrimental effects (40–42). These investigations will be complicated by the effects of some of the drugs on the cellular effectors themselves, the variable effects on the cancer cells depending on their specific mutations, the time frames required to upregulate the responses (about 3 days in the experiments here) and the time required for the effects to wash out of the cancer cells and the effectors.…”

Section: Discussionmentioning

confidence: 99%

Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells

Brea

Manchado

et al. 2016

Cancer Immunology Research

141

114

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The major histocompatibility complex I (MHC-I) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell surface HLA amounts were discovered using a pooled human kinome shRNA interference–based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output–dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases.

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Section: Discussionmentioning

confidence: 99%

Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells

Brea

Manchado

et al. 2016

Cancer Immunology Research

141

114

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“…16 Further in vitro investigation on the effect of MEKi on the different T-cell sub-populations revealed a decrease in proliferation in CD8 C and CD4 C T-cells and a concentration-dependent decline in the generation of antigen-specific T lymphocytes. 17 The investigation of the effect of MEKi on the different T-cell stages revealed a more complex and context-dependent regulation.…”

Section: Meki Effect On T-cellsmentioning

confidence: 99%

MEK inhibition and immune responses in advanced melanoma

et al. 2017

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phase II and III clinical trials demonstrated modest anti- tumor activity of Binimetinib (MEK162) - a potent allosteric inhibitor of MEK1 and MEK2- in patients with advanced NRAS mutant melanoma. The analysis of the NEMO study in NRAS mutated melanoma, has shown that pre-treatment with immunotherapy improved the outcome of binimetinib therapy. We discuss this finding in the context of and effects of MEK inhibition on immuno-critical pathways and interactions.

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“…In contrast, MEK inhibition showed decreased function of DCs including viability and priming capacity in a dose-dependent fashion, suggesting that BRAF inhibition may be preferable to MEK inhibition for optimizing DC cell function. Interestingly, other studies showed that while BRAF and MEK inhibition enhanced DC maturation, it also impaired their ability to cross-present antigens [46, 47]. …”

Section: Key Concepts Underlying the Rationale For Combining Targetedmentioning

confidence: 99%

Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy

2016

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The identification of key driver mutations in melanoma has led to the development of targeted therapies aimed at BRAF and MEK, but responses are often limited in duration. There is growing evidence that MAPK pathway activation impairs antitumor immunity and that targeting this pathway may enhance responses to immunotherapies. There is also evidence that immune mechanisms of resistance to targeted therapy exist, providing the rationale for combining targeted therapy with immunotherapy. Preclinical studies have demonstrated synergy in combining these strategies, and combination clinical trials are ongoing. It is, however, becoming clear that additional translational studies are needed to better understand toxicity, proper timing, and sequence of therapy, as well as the utility of multidrug regimens and effects of other targeted agents on antitumor immunity. Insights gained through translational research in preclinical models and clinical studies will provide mechanistic insight into therapeutic response and resistance and help devise rational strategies to enhance therapeutic responses.

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The kinase inhibitors dabrafenib and trametinib affect isolated immune cell populations

Cited by 13 publications

References 10 publications

Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells

Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells

MEK inhibition and immune responses in advanced melanoma

Influences of BRAF Inhibitors on the Immune Microenvironment and the Rationale for Combined Molecular and Immune Targeted Therapy

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