PTEN and Akt regulation by a Novel Pathway in Lung Cancer

Lung cancer is responsible for 28 percent of all cancer deaths and is a particular concern in Kentucky. Traditional treatment regimens, such as chemotherapy and radiation, attack proliferating cells rather tumor-specific protein targets, resulting in harsh side effects and limited efficacy. The development of targeted therapeutics for lung cancer represents a milestone in lung cancer treatment. One of the primary targets in lung cancer is EGFR (the epidermal growth factor receptor), a trans-membrane tyrosine kinase that drives cell proliferation. The advantage of EGFR inhibitors is that they have relatively few side effects due to the specificity of their targets in tumors. However, the disadvantage is that EGFR inhibitors have a relatively small effect on patient outcomes because tumors quickly develop resistance to them. One of the pathways associated with EGFR inhibitor resistance is directed by PTEN (phosphatase and tensin homologue on chromosome 1 0), a lipid/protein phosphatase that counteracts the activity of the phosphatidyl inositol-3 kinase (PI3K), which activates Akt. A number of genetic studies have linked PTEN to cancer development, but the pathways regulating PTEN are poorly understood. Recently, we have joined in a collaborative effort that identified the Rak tyrosine kinase as a protein that binds and phosphorylates PTEN, stabilizing PTEN and inducing growth arrest. Rak is related to the Src family of tyrosine kinases, with SH2 and SH3 domains at its amino terminus, but Rak has a strikingly different biological activity from its relatives. Rak inhibits growth in a variety of cell types and is expressed in non-malignant lung tissue. However, Rak is not detected in several widely used lung cancer cell lines, and its expression has not been tested in lung tumors. We have found that Rak expression in A549 lung cancer cells induces growth arrest and cell death and causes a profound increase in PTEN levels. Rak is phosphorylated by Src at a key regulatory site in its carboxy terminus, and the hypothesis of the proposal is that the Rak-PTEN tumor suppressor pathway is inhibited by receptor tyrosine kinase signaling in lung cancer cells. As a result, Rak expression may be a marker of decreasing severity in lung cancer samples. We will test the hypotheses with the following specific aims. (1) Determine the extent to which EGFR de-stabilizes PTEN by suppressing Rak activation during lung tumorigenesis. (2) Test the hypothesis that Rak levels in clinical lung tumor samples predicts PTEN levels and responses to traditional therapeutic modalities. The findings will be significant because they will define a new pathway in lung cancer progression. This will ultimately provide a new therapeutic strategy for lung cancer patients, as well as a new biomarker for lung cancer progression.