Data from Lung-Cancer Chemoprevention by Induction of Synthetic Lethality in Mutant <i>KRAS</i> Premalignant Cells <i>In Vitro</i> and <i>In Vivo</i>

<div>Abstract<p>Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of <i>KRAS</i> occur frequently in, and are thought to be a primary driver of the development of, non–small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant <i>KRAS</i> cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and <i>KRAS</i>. Mutational activation of <i>KRAS</i> modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic <i>KRAS</i> repressed cellular FADD-like interleukin 1β–converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame <i>KRAS</i>-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant <i>KRAS</i> cells without harming normal cells. We further showed that short-term, intermittent <i>in vivo</i> treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of <i>KRAS</i>-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC. <i>Cancer Prev Res; 4(5); 666–73. ©2011 AACR</i>.</p></div>