Determinants of Resistance to Erlotinib in NSCLC

表皮生长因子信号转导通路在维持细胞生长的过程中起着重要作用

The epidermal growth factor signal transduction pathway plays an important role in sustaining the growth and survival of certain epithelial malignancies, including non-small cell lung cancer (NSCLC). Erlotinib (Tarceva, OSI-774) is a selective inhibitor of the epidermal growth factor receptor (EGFR)tyrosine kinase that has shown prolongation of survival in a randomized Phase III clinical study in patients with refractory NSCLC and a very tolerable toxicity profile. Results with erlotinib could be markedly improved if patients could be successfully selected based on their tumor molecular determinants of sensitivity and/or resistance to this agent. The main objective of this proposal is to identify the determinants of sensitivity/resistance to erlotinib in freshly resected NSCLC tumors heterotransplanted in nude mice as clinically relevant models of NSCLC. The broad hypothesis being tested is that sensitivityto erlotinib requires a dependence of the tumor for growth and/or survival on the EGFR axis and that resistance to erlotinib is caused by activation of alternative signal transduction pathways. The specific aims are:1. To develop a library of human NSCLC tumors heterotransplanted in nude mice and to assess the degree of genetic similarity between the heterotransplants and the primary tumors resected from the patients. 2. To determine the antitumor activity of erlotinib in NSCLC heterotransplants, to identify molecular determinants of tumor response, stable disease, and tumor progression, and to develop a mathematical algorithm including clinical and molecular parameters to calculate the probability of tumor response/progression with erlotinib therapy in individual patients and,3. To confirm the predictive value of the algorithm in a group of patients with chemoresistant NSCLC selected for their high probability of achieving a response or stable disease with single agent erlotinib therapy.