Oncogenic mutation of epidermal growth factor receptor kinase domain is strongly associated with clinical response to tyrosine kinase inhibitors in non-small-cell lung carcinoma. Despite an initial encouraging response, patients eventually develop drug resistance and relapse. Great efforts have been made to identify the molecular mechanisms of drug resistance. With the recognition of cancer as a whole complex system, here it is proposed that cancer may evolve drug resistance in a cancer-cell-autonomous manner as well as a non-cancer-cell-autonomous manner. The former mainly arises at three levels: the robustness of the epidermal growth factor receptor signaling network; cancer epigenetic changes; or cancer genetic alteration, which may be dependent on the therapeutics methods and treatment duration. As cancer stroma plays an essential role in lung cancerigenesis, we further discuss the potential mechanisms for drug resistance development in a non-cancer-cell-autonomous manner, which may arise from the interaction between cancer cells and cancer stroma, including stromal cells and extracellular matrix.
© 2010 Japanese Cancer Association.