title: An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpesviridae.
abstract: Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3β (GSK-3β), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.
authors.affiliation: INSERM, U1015, Gustave Roussy Institute, Villejuif, France.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Zoubir
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Gdoura
authors.forename: Rastilav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Elena
authors.initials: E
authors.lastname: Litvinova
authors.forename: Vassili
authors.initials: V
authors.lastname: Soumelis
authors.forename: Rosa
authors.initials: R
authors.lastname: Conforti
authors.forename: Sophie
authors.initials: S
authors.lastname: Viaud
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004198:Disease Susceptibility / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006564:Herpesviridae / Q000187:drug effects / Q000502:physiology; D006566:Herpesviridae Infections / Q000139:chemically induced* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011720:Pyrazoles / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; C549971:N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide; D011720:Pyrazoles; D011758:Pyrroles; D051193:Toll-Like Receptors; D018844:Cyclin-Dependent Kinases