| A better understanding of the molecular biology and genetics of these tumors and, in particular, identification of pathways that are amenable to targeting with current therapies are required to make an immediate impact on this difficult to treat disease. Multiple studies have recently shown that the LKB1 gene is inactivated in a third of non-small cell lung cancers. Moreover, inactivation of LKB1 in a mouse model of lung cancer results in more aggressive tumors with a propensity to spread to other organs. We have found that the hypoxia-inducible factor (HIF), a protein involved in the metastatic spread of tumors is activated when LKB1 is lost and, importantly, HIF is necessary for the growth of lung cancer cells lacking LKB1. We therefore hypothesize that HIF is a critical mediator of the aggressiveness of lung cancers that have mutated LKB1. We propose to determine in a large tumor bank of human lung cancers whether HIF activation correlates with LKB1 mutation. Furthermore, with a mouse model of lung cancer, we will determine to what extent HIF mediates the propensity of LKB1 defective lung cancers to spread. These findings will have immediate implications on the treatment of human lung cancer through the use of FDA- approved inhibitors of the HIF pathway.
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