Yixuan Gong M.D.

Recipient of the Barbara Parisi Lung Cancer Research Grant.

Lay Description

Lung cancer is the leading cause of cancer-related death in the US and worldwide. For patients with metastatic non-small cell lung cancer (NSCLC), median survival is 10-12 months with chemotherapy. However, in a subset of NSCLC patients – those whose tumors harbor mutations in the gene encoding the epidermal growth factor receptor (EGFR) – patients can live much longer with fewer side-effects by treatment with selective EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib). Unfortunately, though, despite killing tumor cells, Iressa and Tarceva do not cure patients in the metastatic setting. The overall goal of this proposal is to identify ways to improve even further the outcome of these patients. We believe a better understanding of how mutant EGFR-dependent cells actually “die” when treated with TKIs will help us develop new strategies to enhance drug-induced tumor cell killing. In our preliminary studies, we have identified a molecule whose activation is necessary for Tarceva to induce cell death. Thus, using human lung cancer cell lines, preclinical model systems, and a variety of cellular, biochemical, and molecular techniques, the overall aims of this project are to enhance further our understanding of mechanisms that control TKI-induced cell death and to establish whether drugs that “sensitize” killing by affecting a specific cell death pathway can potentiate TKI-induced killing. Since this new class of drugs is now being tested in early phase clinical trials, our studies could have direct and immediate translational impact.

Scientific Abstract

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.