Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2011
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| Online Access: | http://hdl.handle.net/1721.1/66545 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1811092649511223296 |
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| author | Xue, Wen Meylan, Etienne Oliver, Trudy Feldser, David M. Winslow, Monte Meier Bronson, Roderick T. Jacks, Tyler E. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Xue, Wen Meylan, Etienne Oliver, Trudy Feldser, David M. Winslow, Monte Meier Bronson, Roderick T. Jacks, Tyler E. |
| author_sort | Xue, Wen |
| collection | MIT |
| description | 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 KrasLSL-G12D/wt;p53flox/flox mice but not in KrasLSL-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. |
| first_indexed | 2024-09-23T15:21:27Z |
| format | Article |
| id | mit-1721.1/66545 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:21:27Z |
| publishDate | 2011 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/665452022-10-02T02:25:10Z Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma Xue, Wen Meylan, Etienne Oliver, Trudy Feldser, David M. Winslow, Monte Meier Bronson, Roderick T. Jacks, Tyler E. Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Jacks, Tyler E. Jacks, Tyler E. Xue, Wen Meylan, Etienne Oliver, Trudy Feldser, David M. Winslow, Monte Meier Bronson, Roderick T. 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 KrasLSL-G12D/wt;p53flox/flox mice but not in KrasLSL-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. Howard Hughes Medical Institute National Cancer Institute (U.S.) (Cancer Center Support grant from the NCI (P30-CA14051)) American Association for Cancer Research Leukemia & Lymphoma Society of America Human Frontier Science Program (Strasbourg, France) (Fellowship) American Society for Pharmacology and Experimental Therapeutics Merck Research Laboratories Damon Runyon Cancer Research Foundation Genentech, Inc. 2011-10-24T14:38:14Z 2011-10-24T14:38:14Z 2011-08 Article http://purl.org/eprint/type/JournalArticle 2159-8290 2159-8274 http://hdl.handle.net/1721.1/66545 Richardson, Claire E., Tristan Kooistra, and Dennis H. Kim. “An essential role for XBP-1 in host protection against immune activation in C. elegans.” Nature 463 (2010): 1092-1095. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1158/2159-8290.CD-11-0073 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf American Association for Cancer Research Jacks |
| spellingShingle | Xue, Wen Meylan, Etienne Oliver, Trudy Feldser, David M. Winslow, Monte Meier Bronson, Roderick T. Jacks, Tyler E. Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma |
| title | Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma |
| title_full | Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma |
| title_fullStr | Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma |
| title_full_unstemmed | Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma |
| title_short | Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma |
| title_sort | response and resistance to nf κb inhibitors in mouse models of lung adenocarcinoma |
| url | http://hdl.handle.net/1721.1/66545 https://orcid.org/0000-0001-5785-8911 |
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