Format

Send to

Choose Destination
Sci Transl Med. 2019 Nov 6;11(517). pii: eaaw7852. doi: 10.1126/scitranslmed.aaw7852.

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

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
4
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
5
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
6
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
8
Harvard Medical School, Boston, MA 02115, USA.
9
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. tjacks@mit.edu.

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center