A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors.
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.


CONCLUSIONS
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.
Departments of 1Pediatrics, 2Genetics, and 5Medicine-Oncology, 3Vincent Coates Mass Spectrometry Laboratory, Stanford University, Stanford; and 4Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Cancer Center, University of California Davis School of Medicine, Sacramento, California.
Nadine S
NS
Jahchan
Joel T
JT
Dudley
Pawel K
PK
Mazur
Natasha
N
Flores
Dian
D
Yang
Alec
A
Palmerton
Anne-Flore
AF
Zmoos
Dedeepya
D
Vaka
Kim Q T
KQ
Tran
Margaret
M
Zhou
Karolina
K
Krasinska
Jonathan W
JW
Riess
Joel W
JW
Neal
Purvesh
P
Khatri
Kwon S
KS
Park
Atul J
AJ
Butte
Julien
J
Sage
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019295:Computational Biology; D058492:Drug Repositioning; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000503:physiopathology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D023041:Xenograft Model Antitumor Assays
D000929:Antidepressive Agents, Tricyclic; D000970:Antineoplastic Agents; D043562:Receptors, G-Protein-Coupled