title: Effects of the Janus Kinase Inhibitor, Tofacitinib, on Testicular Leydig Cell Hyperplasia and Adenoma in Rats, and on Prolactin Signaling in Cultured Primary Rat Leydig Cells.
abstract: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity. Since prolactin signals through the JAK2 pathway, we hypothesized that these findings were off-target effects due to inhibition of PRL signaling via JAK2. The studies reported here were designed to investigate the interruption of PRL signaling pathways in Leydig cells. In isolated primary rat Leydig cells, PRL increased phosphorylated Signal Transducer and Activator of Transcription-5 protein, and mRNA levels for luteinizing hormone receptor. Tofacitinib, at concentrations observed in the rat carcinogenicity study, dose-dependently inhibited these effects. These observations illustrate a novel mechanism, the inhibition of prolactin signaling by which modulation of JAK activity can modulate PRL signaling pathways to induce Leydig cell tumors in rats. Since human Leydig cells lack this PRL dependence for normal function, these rodent tumors do not indicate a health risk to human patients.
authors.affiliation: Pfizer Drug Safety R&D, Eastern Point Rd, Groton, Connecticut 06340 robert.e.chapin@pfizer.com.|Pfizer Drug Safety R&D, Eastern Point Rd, Groton, Connecticut 06340.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Chapin
authors.affiliation: Pfizer Drug Safety R&D, Eastern Point Rd, Groton, Connecticut 06340.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Ball
authors.affiliation: Pfizer Drug Safety R&D, 1 Burtt Rd, Andover, Massachusetts 08010.
authors.forename: Zaher A
authors.initials: ZA
authors.lastname: Radi
authors.affiliation: Pfizer Drug Safety R&D, Eastern Point Rd, Groton, Connecticut 06340.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Kumpf
authors.affiliation: Pfizer Drug Safety R&D, Eastern Point Rd, Groton, Connecticut 06340.
authors.forename: Petra H
authors.initials: PH
authors.lastname: Koza-Taylor
authors.affiliation: Pfizer Drug Safety R&D, Eastern Point Rd, Groton, Connecticut 06340.
authors.forename: David M
authors.initials: DM
authors.lastname: Potter
authors.affiliation: Pfizer Drug Safety R&D, 610 Main St, Cambridge, Massachusetts 02139.
authors.forename: W
authors.initials: W
authors.lastname: Mark Vogel
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000818:Animals; D006965:Hyperplasia / Q000139:chemically induced*; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011388:Prolactin / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013737:Testis / Q000187:drug effects* / Q000473:pathology
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D011388:Prolactin
keywords: JAK1/3 inhibitor; LH receptor.; Leydig cell tumor; STAT5; in vitro; primary rat Leydig cell