Leveraging synthetic lethality for effective pyrimidine synthesis targeting in lung adenocarcinoma
Public support
Provider
Czech Science Foundation
Programme
Standard projects
Call for proposals
SGA0202600001
Main participants
Biotechnologický ústav AV ČR, v. v. i.
Contest type
VS - Public tender
Contract ID
26-21754S
Alternative language
Project name in Czech
Leveraging synthetic lethality for effective pyrimidine synthesis targeting in lung adenocarcinoma
Annotation in Czech
Nucleotide metabolism is a key target for cancer therapy, yet inhibitors of dihydroorotate dehydrogenase (DHODH), the best druggable enzyme of pyrimidine synthesis, have shown limited clinical efficacy. Consistently, DHODH loss did not block tumor formation in our orthotopic lung adenocarcinoma model. We hypothesize that co-targeting additional metabolic pathways is required for effective tumor elimination. Our unique preliminary CRISPR screen data from two lung adenocarcinoma cell lines identified co-inhibition of hexosamine biosynthesis, or with pemetrexed, a first line therapy in adenocarcinoma, as synthetically lethal with DHODH loss. This project aims to elucidate mechanisms that underpin these synthetic lethalities using pharmacological and genetic approaches, multi-omics profiling, and in-situ gene-editing in a spontaneous lung tumor model. Our study will uncover fundamental metabolic interactions that drive resistance to pyrimidine synthesis inhibitors, suggesting new therapeutic strategies for lung cancer treatment.
Scientific branches
R&D category
ZV - Basic research
OECD FORD - main branch
10601 - Cell biology
OECD FORD - secondary branch
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OECD FORD - another secondary branch
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CEP - equivalent branches <br>(according to the <a href="http://www.vyzkum.cz/storage/att/E6EF7938F0E854BAE520AC119FB22E8D/Prevodnik_oboru_Frascati.pdf">converter</a>)
EA - Morphology and cytology
Solution timeline
Realization period - beginning
Jan 1, 2026
Realization period - end
Dec 31, 2028
Project status
Z - Beginning multi-year project
Latest support payment
—
Data delivery to CEP
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data delivery code
CEP26-GA0-GA-R
Data delivery date
Apr 27, 2026
Finance
Total approved costs
11,802 thou. CZK
Public financial support
11,802 thou. CZK
Other public sources
0 thou. CZK
Non public and foreign sources
0 thou. CZK