Lung adenocarcinoma: lessons in translation from bench to bedside

Lung cancer is currently the leading cause of cancer-related death in the United States and worldwide, accounting for approximately a third of all cancer diagnoses and deaths. The American Cancer Society estimates 159,390 deaths from lung cancer in the United States for 2009 alone. The high mortality rate associated with lung cancer has prompted numerous exhaustive efforts to identify novel therapeutic targets and treatment modalities for this deadly disease. The characterization of signaling pathways underlying the development and progression of lung cancer, particularly lung adenocarcinoma, has been instrumental in developing novel therapeutic strategies to target aggressive metastatic disease. This paradigm is best illustrated in lung adenocarcinoma by recent studies of the epidermal growth factor receptor, which has been identified to be a critical diagnostic and therapeutic target. Our understanding of the central role of epidermal growth factor receptor in the development and progression of lung adenocarcinoma has led to the development of molecular agents against this key oncogene that have demonstrated significant clinical efficacy against the disease. Despite these successes, de novo or acquired resistance to these anti-epidermal growth factor receptor agents invariably develops, either through additional mutations in the epidermal growth factor receptor, or abnormal regulation of downstream signaling pathways. Thus, it is necessary to further investigate the molecular determinants of treatment resistance and to develop novel therapeutic strategies directed specifically against the molecular drivers of metastatic chemoresistant lung cancer. Given the heterogeneity and convergence of signaling pathways underlying both disease etiology and chemoresistance, future efforts to administer rationally designed agents against multiple molecular targets could serve to improve both first-line and second-line therapies for patients with lung adenocarcinoma.