Lung cancer arises due to defects in tumor suppressor genes which inhibit tumor growth, and oncogenes, which promote tumor growth. One type of tumor suppressor whose malfunction is crucial for the origin and spread of lung cancer is the p53 gene. The p53 gene has been found to be mutated or genetically deleted in over 50 percent of lung cancers. We have identified 14 genes that when blocked can selectively eradicate p53-deficient lung cancer cells in a large percentage of patients. We will determine which of these genes can be targeted for the treatment of p53-deficient lung cancers using cell cultures and mouse models. The results of our experiments will provide a new but effective treatment option for many lung cancers patients, including those with metastatic and drug-resistant lung cancers.