Research ArticleCancer

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

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Science Translational Medicine  06 Nov 2019:
Vol. 11, Issue 517, eaaw7852
DOI: 10.1126/scitranslmed.aaw7852

A big step against small cell cancer

Small cell lung cancer is a particularly aggressive tumor subtype, for which no specific targeted treatments are available. Li et al. used a CRISPR screening approach to identify a metabolic vulnerability and determine that small cell lung cancer cells are particularly reliant on the pyrimidine biosynthesis pathway and therefore sensitive to its disruption. The authors then demonstrated that brequinar, a pharmacological inhibitor of a key step in this pathway, is effective against small cell lung cancer in vitro and in multiple mouse models, including patient-derived xenografts.

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.

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