title: Everolimus exhibits efficacy as a radiosensitizer in a model of non-small             cell lung cancer.
abstract: Signaling pathways that activate mTOR (mammalian target of rapamycin) are             altered in many human cancers and these alterations are associated with prognosis             and treatment response. mTOR inhibition can restore sensitivity to DNA damaging             agents such as cisplatin. The rapamycin derivative everolimus exhibits antitumor             activity and is approved for patients with renal cell cancer. Clinically, everolimus             has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC)             that were refractory to chemotherapy and epidermal growth factor receptor tyrosine             kinase inhibitors. We tested the effects of combined treatment with everolimus             (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549             cells). In growth studies, mean tumor volume was reduced in the everolimus plus             30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone             (p=0015), or everolimus alone (p<0.001, ANOVA). everolimus (20 nM) significantly             reduced protein levels of the mTOR downstream effector p70-S6K compared with radiation             and vehicle (p=0.05, ANOVA) and significantly suppressed phospho-p70-S6K levels             compared with all other treatments (p<0.001, ANOVA). We also evaluated everolimus             and radiation effects on gene expression in A549 cells. Everolimus ± 5 Gy suppressed             endothelin 1 and lactate dehydrogenase expression and increased VEGFA, p21, hypoxia-inducible             factor-1α and SLC2A1 (facilitated glucose transporter 1). mTOR mRNA levels were             unaffected while TNF-α levels were increased with everolimus + 5 Gy compared to             either treatment alone. These findings suggest that everolimus increases the antitumor             activity of radiation. Clinical trials combining everolimus with fractionated             radiation in patients with NSCLC are warranted.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA. hjmaucer@uchicago.edu
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: Harold G
authors.initials: HG
authors.lastname: Sutton
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: Masha
authors.initials: M
authors.lastname: Kocherginsky
authors.forename: Joel
authors.initials: J
authors.lastname: Kochanski
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000068338:Everolimus; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; D000068338:Everolimus; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus