| First Author | Xue W | Year | 2011 |
| Journal | Cancer Discov | Volume | 1 |
| Issue | 3 | Pages | 236-47 |
| PubMed ID | 21874163 | Mgi Jnum | J:185637 |
| Mgi Id | MGI:5429505 | Doi | 10.1158/2159-8290.CD-11-0073 |
| Citation | Xue W, et al. (2011) Response and resistance to NF-kappaB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov 1(3):236-47 |
| abstractText | Lung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-kappaB 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-kappaB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-kappaB activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-kappaB 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-kappaB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-kappaB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma. SIGNIFICANCE: Using small-molecule compounds that inhibit NF-kappaB activity, we provide evidence that NF-kappaB 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. |
