Somatic mutations in the EGF receptor (EGFR) gene are associated with increased sensitivity of lung cancers to tyrosine kinase inhibitors (TKIs) like erlotinib and gefitinib.  However, these drugs still do not cure responding patients with metastatic disease.  Understanding how mutant EGFR cells actually respond to treatment should allow for the identification of new targets and strategies to achieve even better clinical outcomes. In our studies, we have found that in lung adenocarcinomas that depend upon mutant EGFR for survival, TKIs kill cells by specifically initiating the intrinsic pathway of caspase activation. Apoptosis requires induction of the pro-apoptotic BH3-only protein, BIM, as knockdown of BIM expression by RNA interference completely eliminates drug-induced cell killing in vitro, and cells that are sensitive to treatment but that do not die do not display BIM induction.  This observation suggests that the intrinsic pathway of apoptosis could be exploited to potentiate responses of mutant EGFR-dependent cells to kinase inhibitors. Indeed, our preliminary studies with the BCL-2 antagonist, ABT-737, demonstrate that this drug can enhance the sensitivity of EGFR mutant cells to erlotinib.  Therefore, the goal of this project is to further expand our knowledge regarding mechanisms of TKI-induced cell death, in order to identify new targets and strategies to enhance drug-induced killing. Specifically, we aim 1) to determine key EGFR downstream signaling pathways involved in BIM activation by erlotinib, 2) to uncover additional pathways and molecules involved in erlotinib-induced apoptosis, and 3) to determine the efficacy in vitro and in vivo of the anti-apoptotic inhibitor, ABT-737, in the treatment of EGFR mutant lung adenocarcinomas, either as a single agent or in conjunction with erlotinib.