Data from Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma

Abstract

<div>Abstract<p>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 <i>Kras</i><sup>LSL-G12D/wt</sup>;<i>p53</i><sup><i>flox/flox</i></sup> mice but not in <i>Kras</i><sup><i>LSL-G12D/wt</i></sup> 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.</p><p><b>Significance:</b> 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 <i>in vivo</i> and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer. <i>Cancer Discovery; 1(3)</i>; 236–47. <i>© 2011 AACR.</i></p><p>Read the Commentary on this article by Van Waes, p. 200</p><p>This article is highlighted in the In This Issue feature, p. 189</p></div>