Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 11, Issue 517, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw7852
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Funding
- Howard Hughes Medical Institute
- Ludwig Center for Molecular Oncology at MIT
- Koch Institute Support (core) Grant from the National Cancer Institute [P30-CA14051]
- Swiss National Science Foundation (SNSF)
- Hope Funds Postdoctoral Fellowship
- A*STAR (Agency for Science, Technology and Research, Singapore) National Science Scholarship
- MIT School of Science Fellowship in Cancer Research
- NIH [U01CA220323]
- SU2C
- MIT Center for Precision Cancer Medicine [R01CA168653, R01-CA201276]
- NCI Mentored Clinical Scientist Research Career Development Award [K08CA208016]
- KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources) [KL2 TR001100]
- KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences) [KL2 TR001100]
- Conquer Cancer Foundation-American Society for Clinical Oncology (CCF-ASCO) Young Investigator Award
- NIH Loan Repayment Program
- [2T32CA071345-21A1]
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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 similar to 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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