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Identification of DHODH as a therapeutic target in small cell lung cancer
Leanne Li1, Sheng Rong Ng1,2, Caterina I Colón1
1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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.
Insights
Researchers identified a new vulnerability in aggressive small cell lung cancer (SCLC). Inhibiting dihydroorotate dehydrogenase (DHODH) shows promise for treating SCLC by targeting pyrimidine biosynthesis.
Area of Science:
- Oncology
- Genetics
- Biochemistry
Background:
- Small cell lung cancer (SCLC) is an aggressive subtype with a poor prognosis.
- Limited targeted therapies exist due to a lack of identified genetic drivers.
- The treatment options for SCLC have seen minimal advancement for decades.
Purpose of the Study:
- To identify novel genetic vulnerabilities in SCLC using a CRISPR-based screening approach.
- To discover potential therapeutic targets for SCLC treatment.
- To find SCLC-selective vulnerabilities through cross-cancer analysis.
Main Methods:
- Utilized a CRISPR loss-of-function screen with a sgRNA library targeting ~5000 druggable genes.
- Performed screens in cell lines from autochthonous genetically engineered mouse models (GEMMs) of SCLC, LUAD, and PDAC.
- Conducted cross-cancer analyses to pinpoint SCLC-specific vulnerabilities.
Main Results:
- Identified enhanced sensitivity in SCLC cells upon disruption of the pyrimidine biosynthesis pathway.
- Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH) reduced SCLC cell viability in vitro.
- DHODH inhibition strongly suppressed SCLC tumor growth in patient-derived xenograft (PDX) and autochthonous mouse models.
Conclusions:
- Disruption of pyrimidine biosynthesis represents a key vulnerability in SCLC.
- Dihydroorotate dehydrogenase (DHODH) is a potential therapeutic target for SCLC.
- DHODH inhibition offers a promising new therapeutic strategy for treating small cell lung cancer.
