Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer

  • Authors:
    • Helena J. Mauceri
    • Harold G. Sutton
    • Thomas E. Darga
    • Masha Kocherginsky
    • Joel Kochanski
    • Ralph R. Weichselbaum
    • Everett E. Vokes
  • View Affiliations

  • Published online on: January 27, 2012     https://doi.org/10.3892/or.2012.1666
  • Pages: 1625-1629
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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.

Related Articles

Journal Cover

May 2012
Volume 27 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Mauceri H , Sutton HG, Darga TE, Kocherginsky M, Kochanski J, Weichselbaum RR and Vokes EE: Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer. Oncol Rep 27: 1625-1629, 2012
APA
Mauceri, H. ., Sutton, H.G., Darga, T.E., Kocherginsky, M., Kochanski, J., Weichselbaum, R.R., & Vokes, E.E. (2012). Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer. Oncology Reports, 27, 1625-1629. https://doi.org/10.3892/or.2012.1666
MLA
Mauceri, H. ., Sutton, H. G., Darga, T. E., Kocherginsky, M., Kochanski, J., Weichselbaum, R. R., Vokes, E. E."Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer". Oncology Reports 27.5 (2012): 1625-1629.
Chicago
Mauceri, H. ., Sutton, H. G., Darga, T. E., Kocherginsky, M., Kochanski, J., Weichselbaum, R. R., Vokes, E. E."Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer". Oncology Reports 27, no. 5 (2012): 1625-1629. https://doi.org/10.3892/or.2012.1666