William Y. Kim M.D.

This grant is being fully funded by the Thomas G. Labrecque Foundation, through the Uniting Against Lung Cancer Grant Program.

Lay Description

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.

Scientific Abstract

Molecular analysis of lung carcinomas has identified a small number of genetic lesions, such as activation of oncogenes and inactivation of tumor suppressor genes, that appear to be critical for their development and maintenance. Recently, somatic mutations of the LKB1 tumor suppressor gene have been added to this list. In a mouse model of lung adenocarcinoma, LKB1 deletion on a backdrop of mutant Kras activation results in a shorter tumor latency, an expanded histological spectrum, and a propensity towards metastasis. We have observed that the hypoxia-inducible factor (HIF) family member, HIF2, is upregulated upon LKB1 loss and that in LKB1-deficient lung cancer cell lines knock-down of HIF2 results in the induction of markers of apoptosis, suggesting that HIF2 mediates the survival of LKB1-deficient lung cancers. We hypothesize that HIF2 is a critical downstream mediator of LKB1 loss and propose: 1) To determine whether HIF2 activation correlates with LKB1 mutation in a large dataset of human lung tumors. 2) To determine whether the phenotype induced by LKB1 loss is dependent upon HIF2 in vitro. 3) To determine whether the phenotypes induced by LKB1 loss are dependent upon HIF2 in vivo.