Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy.
The mammalian target of rapamycin (mTOR) modulates key signaling pathways that promote uncontrolled proliferation of glioblastoma multiforme (GBM). Because rapid tumor proliferation may contribute to the clinical radioresistance of GBM tumors, the combination of rapamycin, a selective mTOR inhibitor, and radiation was studied in vitro and in vivo in a GBM model. In monolayer cultures of U87 and SKMG-3 cells, rapamycin had no impact on radiation sensitivity. In contrast, rapamycin significantly enhanced the efficacy of fractionated radiation of established U87 xenografts in nude mice. Similar effects were seen in U87 spheroids treated with rapamycin and radiation, which suggests that the sensitizing effects of this drug are dependent on disruption of mTOR signaling pathways specifically within tumor cells. Inhibition of these signaling pathways can lead to inhibition of G(1)-specific cyclin-dependent kinase activities, and this could contribute to the sensitizing effects of rapamycin. Consistent with this idea, roscovitine, a specific cyclin-dependent kinase inhibitor, also enhanced the efficacy of fractionated radiation in U87 spheroids. These data demonstrate that inhibition of tumor proliferation does not diminish the efficacy of fractionated radiation and suggest that disruption of key signal transduction pathways may significantly enhance the effectiveness of radiation therapy in malignant gliomas.
Eshleman
Jeffrey S
JS
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Carlson
Brett L
BL
Mladek
Ann C
AC
Kastner
Brian D
BD
Shide
Kathleen L
KL
Sarkaria
Jann N
JN
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D018874:Spheroids, Cellular; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus