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Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma.

Publication ,  Journal Article
Xue, W; Meylan, E; Oliver, TG; Feldser, DM; Winslow, MM; Bronson, R; Jacks, T
Published in: Cancer Discov
August 2011

UNLABELLED: Lung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-κB pathway affects both the initiation and the maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this investigation, we tested the efficacy of small-molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes, and rapidly induced apoptosis. Bortezomib also induced lung tumor regression and prolonged survival in tumor-bearing Kras(LSL-G12D/wt);p53(flox/flox) mice but not in Kras(LSL-G12D/wt) mice. After repeated treatment, initially sensitive lung tumors became resistant to bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma. SIGNIFICANCE: Using small-molecule compounds that inhibit NF-κB activity, we provide evidence that NF-κB inhibition has therapeutic efficacy in the treatment of lung cancer. Our results also illustrate the value of mouse models in validating new drug targets in vivo and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer.

Duke Scholars

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

August 2011

Volume

1

Issue

3

Start / End Page

236 / 247

Location

United States

Related Subject Headings

  • Transcription Factor RelA
  • Survival Rate
  • Sulfones
  • Signal Transduction
  • Pyrazines
  • Nitriles
  • NF-kappa B
  • Mice, 129 Strain
  • Mice
  • Lung Neoplasms
 

Citation

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Xue, W., Meylan, E., Oliver, T. G., Feldser, D. M., Winslow, M. M., Bronson, R., & Jacks, T. (2011). Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov, 1(3), 236–247. https://doi.org/10.1158/2159-8290.CD-11-0073
Xue, Wen, Etienne Meylan, Trudy G. Oliver, David M. Feldser, Monte M. Winslow, Roderick Bronson, and Tyler Jacks. “Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma.Cancer Discov 1, no. 3 (August 2011): 236–47. https://doi.org/10.1158/2159-8290.CD-11-0073.
Xue W, Meylan E, Oliver TG, Feldser DM, Winslow MM, Bronson R, et al. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov. 2011 Aug;1(3):236–47.
Xue, Wen, et al. “Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma.Cancer Discov, vol. 1, no. 3, Aug. 2011, pp. 236–47. Pubmed, doi:10.1158/2159-8290.CD-11-0073.
Xue W, Meylan E, Oliver TG, Feldser DM, Winslow MM, Bronson R, Jacks T. Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov. 2011 Aug;1(3):236–247.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

August 2011

Volume

1

Issue

3

Start / End Page

236 / 247

Location

United States

Related Subject Headings

  • Transcription Factor RelA
  • Survival Rate
  • Sulfones
  • Signal Transduction
  • Pyrazines
  • Nitriles
  • NF-kappa B
  • Mice, 129 Strain
  • Mice
  • Lung Neoplasms