Induction of Synthetic Lethality In Mutant Kras Cells For Non-Small Cell Lung Cancers Chemoprevention and Therapy

<p>Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Despite improvement in treatment strategies, the 5-year survival rate of lung cancer patients remains low. Thus, effective chemoprevention and treatment approaches are sorely needed. Mutations and activation of KRAS occur frequently in tobacco users and the early stage of development of non-small cell lung cancers (NSCLC). So they are thought to be the primary driver for lung carcinogenesis. My work showed that <em>KRAS</em> mutations and activations modulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors by up-regulating death receptors and down-regulating decoy receptors. In addition, we showed that KRAS suppresses cellular FADD-like IL-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of ERK/MAPK-mediated activation of c-MYC which means the mutant <em>KRAS</em> cells could be specifically targeted via TRAIL induced apoptosis. The expression level of Inhibitors of Apoptosis Proteins (IAPs) in mutant <em>KRAS</em> cells is usually high which could be overcome by the second mitochondria-derived activator of caspases (Smac) mimetic. So the combination of TRAIL and Smac mimetic induced the synthetic lethal reaction specifically in the mutant-KRAS cells but not in normal lung cells and wild-type <em>KRAS</em> lung cancer cells. Therefore, a synthetic lethal interaction among TRAIL, Smac mimetic and <em>KRAS</em> mutations could be used as an approach for chemoprevention and treatment of NSCLC with <em>KRAS </em>mutations. Further data in animal experiments showed that short-term, intermittent treatment with TRAIL and Smac mimetic induced apoptosis in mutant <em>KRAS</em> cells and reduced tumor burden in a KRAS-induced pre-malignancy model and mutant <em>KRAS</em> NSCLC xenograft models. These results show the great potential benefit of a selective therapeutic approach for the chemoprevention and treatment of NSCLC with <em>KRAS</em> mutations.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Huang, Shaoyi

Contributors dc:contributor

• Xiangwei Wu
• Carlos Caulin
• Bingliang Fang

• NSCLC
• KRAS
• Synthetic lethality
• Chemoprevention
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/396

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1436