title: Cytokines can counteract the inhibitory effect of MEK-i on NK-cell function.
abstract: Oncogene-targeted therapies based on mutated BRAF- and/or MEK-specific inhibitors have been developed for melanoma treatment. Although these drugs induce tumor regression in a high percentage of patients, clinical responses are frequently limited in time and tumors often recur. Recent studies suggested that the combination of BRAF/MEK inhibition with immunotherapy could represent a promising strategy for the cure of melanoma. NK cells are suitable effectors for tumor immunotherapy. Here we show that PLX4032 (a mutant BRAFV600 inhibitor) had no effect on the functional properties of NK cells cultured in the presence of IL-2 or IL-15. In contrast, PD0325901 (a MEK inhibitor) induced the down-regulation of the main activating NK receptors and inhibited NK cell function. Importantly, PD0325901 did not affect the anti-tumor activity of NK cells that had been exposed to a combination of IL-15 and IL-18. In addition, both PLX4032 and PD0325901 did not exert any inhibitory effect on in vitro IL-2 or IL-15 pre-activated NK cells.Our data may provide a rationale for future clinical protocols that combine IL-15/IL-18 cytokine administration with MEK inhibitors. In addition, they suggest that oncogene-targeting drugs are compatible with NK-based adoptive therapy.
authors: IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors: Claudia
authors: C
authors: Manzini
authors: Oncologia Molecolare e Angiogenesi, IRCCS AOU San Martino-IST, Genoa, Italy.
authors: Roberta
authors: R
authors: Venè
authors: IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors: Irene
authors: I
authors: Cossu
authors: Anatomia Patologica, IRCCS AOU San Martino-IST, Genoa, Italy.
authors: Marina
authors: M
authors: Gualco
authors: Diagnostica Molecolare, IRCCS AOU San Martino-IST, Genoa, Italy.
authors: Simonetta
authors: S
authors: Zupo
authors: Diagnostica Molecolare, IRCCS AOU San Martino-IST, Genoa, Italy.
authors: Mariella
authors: M
authors: Dono
authors: Oncologia Medica 2, IRCCS AOU San Martino-IST, Genoa, Italy.
authors: Francesco
authors: F
authors: Spagnolo
authors: Oncologia Medica 2, IRCCS AOU San Martino-IST, Genoa, Italy.
authors: Paola
authors: P
authors: Queirolo
authors: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors: Lorenzo
authors: L
authors: Moretta
authors: Immunologia, IRCCS AOU San Martino-IST, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors: Maria Cristina
authors: MC
authors: Mingari
authors: Immunologia, IRCCS AOU San Martino-IST, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors: Gabriella
authors: G
authors: Pietra
mesh_terms: D000181:Acrylonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D007211:Indoles / Q000494:pharmacology; D019409:Interleukin-15 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009857:Oncogenes; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; C569274:IL15 protein, human; C508594:IL2 protein, human; D007211:Indoles; D019409:Interleukin-15; D007376:Interleukin-2; C000610759:MEK inhibitor I; D013449:Sulfonamides; D000077484:Vemurafenib; C506614:mirdametinib; D004159:Diphenylamine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000181:Acrylonitrile
keywords: BRAF/MEK inhibitors; Immune response; Immunity; Immunology and Microbiology Section; NK cells; cytokines; immunotherapy; melanoma