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Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein–coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.Significance: Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells. Cancer Discov; 3(12); 1364–77. ©2013 AACR.See related commentary by Wang and Byers, p. 1333This article is highlighted in the In This Issue feature, p. 1317

PDF file 980K, Expression levels of the ligands of the GPCRs targeted by the TCAs and the enzymes required for their biosynthesis in SCLC cells

PDF file 94K, Top 100 FDA-approved drugs identified by a bioinformatics drug- repositioning approach

PDF file 779K, Induction of cell death in SCLC cells after treatment with related TCAs and with specific GPCR inhibitors

PDF file 745K, Expression levels of the GPCRs that are the targets of tricyclic antidepressants

PDF file 2897K, Molecular mechanisms leading to the cell death induced by the drugs

PDF file 2159K, Inhibitory effects of imipramine, promethazine, and bepridil on SCLC cells in culture

Supplementary Figure S2 - PDF file 1676K, Induction of cell death and decreased proliferation following imipramine and promethazine treatment

PDF file 114K, This document provides detailed information on some of the methods employed in our manuscript

SummarySmall cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)–approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein–coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. Significance: Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells. Cancer Discov; 3(12); 1364–77. ©2013 AACR. See related commentary by Wang and Byers, p. 1333 This article is highlighted in the In This Issue feature, p. 1317

Lung cancer is the leading cause of cancer deaths worldwide, with more than 1.3 million deaths annually. SCLC is a subtype of lung cancer representing ∼15% of all lung cancer cases, and is characterized by the rapid expansion and metastasis of small cells with neuroendocrine features. Patients are typically treated with 4-6 rounds of etoposide and a platinum-based agent, to which there is a 30-40% complete response rate. However, patients almost invariably relapse with disease that is resistant to their primary therapy, and rapidly succumb to their malignancy due to this chemoresistance. No targeted therapy has ever been approved despite numerous attempts. Consequently, 5-year survival for patients has hovered near 5% for the last 30 years. Drug repositioning, which is the discovery of new indications for existing drugs, is an increasingly attractive mode of therapeutic discovery. Recent advances in computing, concomitant with the increasing availability of large datasets, have enabled the development of in silico approaches to drug discovery. Here we applied a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat small cell lung cancer (SCLC). We found that tricyclic antidepressants (TCAs) and related molecules, such as imipramine and promethazine, potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine/paracrine survival signals involving neurotransmitters and their receptors. In particular, the mechanism of action of these drugs in inhibiting SCLC tumor growth is through antagonizing G- protein coupled receptors (GPCRs) and blocking signaling downstream, leading to a decrease in cAMP levels and PKA activity, subsequently resulting in activation of the c-Jun/JNK pathway. Moreover, TCAs induce rapid cell death in other neuroendocrine tumors, including carcinoid tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. Since these drugs have already been vetted in terms of safety, dosage and toxicity, they can rapidly enter clinical trials. Citation Format: Nadine S. Jahchan, Joel T. Dudley, Pawel K. Mazur, Natasha Flores, Dian Yang, Alec Palmerton, Anne-Flore Zmoos, Dedeepya Vaka, Kim Q.t. Tran, Margaret Zhou, Karolina Krasinska, Jonathan W. Riess, Joel W. Neal, Purvesh Khatri, Kwon S. Park, Atul J. Butte, Julien Sage. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4610. doi:10.1158/1538-7445.AM2014-4610