Role of mTOR Inhibitors in Growth Hormone-Producing Pituitary Adenomas Harboring Different FGFR4 Genotypes.
Pituitary adenomas (PAs) are common intracranial lesions. Available medical therapies are limited in PAs, and therefore, it is essential to identify treatments that control PA growth when surgery is not an option. Fibroblast growth factor 4 is implicated in PA pathogenesis; therefore, in this study, we used an isogenic mammosomatotroph cell line (GH4C1) harboring different fibroblast growth factor receptor (FGFR)-4 genotypes to establish and characterize intracranial xenograft mouse models that can be used for preclinical drug testing. We show that proliferating GH4C1 tumors have an average latency of 3 weeks to form. Histological analysis revealed that prototypic FGFR4 (G388) tumors express increased prolactin and less GH, whereas tumors possessing the polymorphic variant of FGFR4 (R388) express increased GH relative to prolactin. All tumors show abundant mammalian target of rapamycin (mTOR) signaling as confirmed using phosphorylated (p)-S6 and p-4E-binding protein 1 as downstream regulators of this pathway. We subsequently demonstrate that the mTOR inhibitor RAD001 decreases tumor growth rate and reduces p-S6 but not p-4E-binding protein 1 activation, regardless of FGFR4 status. More importantly, GH activity was significantly reduced after mTOR inhibition in the R388 polymorphic variant tumors. This reduction was also associated with a concomitant reduction in serum IGF-1 levels in the R388 group. In summary, we demonstrate that the GH4C1 FGFR polymorphic xenograft is a useful model for examining PAs. Furthermore, we show that RAD001 can efficiently reduce tumor growth rate by a reduction in mTOR signaling and more importantly results in control of GH expression and IGF-1 secretion, providing further support for using mTOR inhibitors in PA patients, in particular GH-producing adenomas.
McFeeters-Hamilton Center for Neuro-Oncology Research (S.J., E.M., G.Z.), Princess Margaret Cancer Center (S.J., E.M., T.T., G.Z.), and Division of Neurosurgery (G.Z.), Toronto Western Hospital, Toronto, Canada M5T 2S8.
Shahrzad
S
Jalali
McFeeters-Hamilton Center for Neuro-Oncology Research (S.J., E.M., G.Z.), Princess Margaret Cancer Center (S.J., E.M., T.T., G.Z.), and Division of Neurosurgery (G.Z.), Toronto Western Hospital, Toronto, Canada M5T 2S8.
Eric
E
Monsalves
McFeeters-Hamilton Center for Neuro-Oncology Research (S.J., E.M., G.Z.), Princess Margaret Cancer Center (S.J., E.M., T.T., G.Z.), and Division of Neurosurgery (G.Z.), Toronto Western Hospital, Toronto, Canada M5T 2S8.
Toru
T
Tateno
McFeeters-Hamilton Center for Neuro-Oncology Research (S.J., E.M., G.Z.), Princess Margaret Cancer Center (S.J., E.M., T.T., G.Z.), and Division of Neurosurgery (G.Z.), Toronto Western Hospital, Toronto, Canada M5T 2S8.
Gelareh
G
Zadeh
D000818:Animals; D002460:Cell Line; D000068338:Everolimus / Q000494:pharmacology / Q000627:therapeutic use; D013006:Growth Hormone / Q000378:metabolism; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D038601:Ribosomal Protein S6; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D000068338:Everolimus; D051499:Receptor, Fibroblast Growth Factor, Type 4; D058570:TOR Serine-Threonine Kinases