Open AccessIdentification of DHODH as a therapeutic target in small cell lung cancer
Author(s) -
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 C. Beytagh,
Anna F. Farago,
Matthew G. Vander Heiden,
Nicholas J. Dyson,
Tyler Jacks
Publication year - 2019
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aaw7852
Subject(s) - druggability , cancer research , biology , dihydroorotate dehydrogenase , adenocarcinoma , phenotype , crispr , cancer , gene , pyrimidine metabolism , lung cancer , medicine , genetics , enzyme , oncology , biochemistry , pyrimidine , purine
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.