Small cell lung carcinoma (SCLC) is highly aggressive and metastatic neuroendocrine lung cancer with a dismal 5-year survival. While a majority of patients is initially responsive to chemotherapy, chemoresistant tumors rapidly recur. There are no approved targeted therapies for SCLC. We used a systematic drug-repurposing computational approach querying a large number of gene expression datasets to identify new candidate FDA-approved drugs that may be used to treat SCLC. This analysis identified tricyclic antidepressants (TCAs) and related molecules as possible inhibitors of SCLC. Indeed, these compounds potently induce apoptotic cell death in chemonaïve and chemoresistant tumor cells in culture, in a genetically engineered mouse model, and in human SCLC tumor cells transplanted into immunocompromised mice. Imipramine and Promethazine, the two top candidate drugs, activate stress pathways and induce apoptosis and necrosis in SCLC cells, in part by blocking autocrine survival signals involving neurotransmitters and their receptors (GPCRs). The candidate drugs inhibit the expansion of other neuroendocrine tumors, including pancreatic neuroendocrine tumors. These experiments underscore the power of bioinformatics-based drug-repositioning approaches to rapidly repurpose FDA-approved drugs and identify a novel class of candidate molecules to treat patients with SCLC. In addition, our experiments highlight the importance of autocrine mechanisms promoting the growth of neuroendocrine tumor cells.

Citation Format: Nadine Jahchan, Dudley Joel, Pawel Mazur, Joel Neal, Purvesh Khatri, Atul Butte, Julien Sage. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA02.

©2014 American Association for Cancer Research.
2014