Identification of DHODH as a therapeutic target in small cell lung cancer

Leanne Li, Sheng Rong Ng, Caterina I. Colón, Benjamin J. Drapkin, Peggy P. Hsu, Zhaoqi Li, Christopher S. Nabel, Caroline A. Lewis, Rodrigo Romero, Kim L. Mercer, Arjun Bhutkar, Sarah Phat, David T. Myers, Mandar Deepak Muzumdar, Peter M.K. Westcott, Mary Clare Beytagh, Anna F. Farago, Matthew G.Vander Heiden, Nicholas J. Dyson, Tyler Jacks

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with extremely poor prognosis. No targetable genetic driver events have been identified, and the treatment landscape for this disease has remained nearly unchanged for over 30 years. Here, we have taken a CRISPR-based screening approach to identify genetic vulnerabilities in SCLC that may serve as potential therapeutic targets. We used a single-guide RNA (sgRNA) library targeting ~5000 genes deemed to encode "druggable" proteins to perform loss-of-function genetic screens in a panel of cell lines derived from autochthonous genetically engineered mouse models (GEMMs) of SCLC, lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). Cross-cancer analyses allowed us to identify SCLC-selective vulnerabilities. In particular, we observed enhanced sensitivity of SCLC cells toward disruption of the pyrimidine biosynthesis pathway. Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, reduced the viability of SCLC cells in vitro and strongly suppressed SCLC tumor growth in human patient-derived xenograft (PDX) models and in an autochthonous mouse model. These results indicate that DHODH inhibition may be an approach to treat SCLC.

Original languageEnglish (US)
Article numbereaaw7852
JournalScience translational medicine
Volume11
Issue number517
DOIs
StatePublished - Nov 6 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Li, L., Ng, S. R., Colón, C. I., Drapkin, B. J., Hsu, P. P., Li, Z., Nabel, C. S., Lewis, C. A., Romero, R., Mercer, K. L., Bhutkar, A., Phat, S., Myers, D. T., Muzumdar, M. D., Westcott, P. M. K., Beytagh, M. C., Farago, A. F., Heiden, M. G. V., Dyson, N. J., & Jacks, T. (2019). Identification of DHODH as a therapeutic target in small cell lung cancer. Science translational medicine, 11(517), [eaaw7852]. https://doi.org/10.1126/scitranslmed.aaw7852