Non-small cell lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer-related death in the U.S. expected to be diagnosed in more than 150,000 patients this year alone. For patients presenting with localized disease surgical resection of primary tumor is the primary therapy with curative intent. However, the majority of patients present with advanced disease and therapeutic options are limited to chemo- and radiotherapy. Intervention by these procedures has shown only limited success such that even the most successful therapies result in 20% response rates due to the relative resistance of NSCLC to these therapies with respect to other forms of lung cancer and to the common molecular changes which are associated with this disease. Therefore there is a desperate need to improve existing therapy or increase therapeutic options. The molecular characteristics of this disease have provided valuable insight into the limited sensitivity of these tumors to chemotherapy since the majority of NSCLC tumors (more than 60%) express mutations or deletions in the tumor suppressor p53 gene. Loss of function of the p53 protein correlates in many tumor types with decreased sensitivity to apoptosis-based therapies such as DNA-damaging drugs or radiation. This disease is also characterized by its increased expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFr, more than 60%) and HER2/Neu (more than 20%), which suggest increased tumor growth and metastatic potential. However, preliminary studies of squamous carcinoma cells with inactive p53 protein suggested that increased cellular apoptotic sensitivity to DNA-interactive drugs like cis-platinum (cDDP) and camptothecin (CPT) is associated with high expression of EGFr and a reduction in DNA repair capacity. Reciprocally, resistance to cDDP (or CPT) was associated with down-regulation of EGFr, reduced growth rate and increased DNA repair activity. Interestingly, there was also increased expression of a cell-cycle checkpoint protein, p21/WAF-1, in cDDP-resistant tumor cells which, although inducible by p53 accumulation in damaged cells, was not associated with any change in p53 expression. Importantly, EGF stimulation of cells increased their sensitivity to cDDP by 3-fold suggesting potential regulation of cDDP sensitivity by receptor tyrosine kinase pathways in p53 deficient cells. The short-term goal of this study is to examine the regulation of specific drug sensitivities in NSCLC cells with mutations in the their p53 gene by modulating expression of receptor tyrosine kinases. The long term goal of this project is to define NSCLC tumor cell characteristics which allow increased sensitivity to chemotherapy by modulation of signaling pathways prior to clinical testing in at least a subset of qualified NSCLC patients.
