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Targeting DHFR to suppress 1-C metabolism and enhance radiation sensitivity in NRF2-active head and neck squamous cell carcinoma

ABSTRACT: NRF2 hyperactivity is associated with radiation resistance in head and neck squamous cell carcinoma (HNSCC). We evaluated the dihydrofolate reductase (DHFR) inhibitors pyrimethamine and its potent analog, WCDD115, as radiosensitizing agents through disruption of one-carbon metabolism.Preclinical studies used NRF2-competent and deficient HNSCC models, clonogenic assays, transcriptomics, metabolomics, pharmacokinetics/toxicity testing, and syngeneic tumor grafts to assess WCDD115 as a novel radiosensitizing agent. Correlative analysis included mass spectrometry, western blotting, and pathway analysis. WCDD115 enhanced radiation-induced DNA damage and suppressed one-carbon metabolism and nucleotide biosynthesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE345515 | GEO | 2026/09/04

REPOSITORIES: GEO

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Pyrimethamine and a potent analogue WCDD115 inhibit NRF2 by suppressing DHFR and one-carbon metabolism

Project description:Nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2) is a critical mediator of the cellular oxidative stress response. Aberrant activation of NRF2 is common in many lung and upper aerodigestive cancers, where it promotes tumor progression and confers resistance to chemotherapy, radiation therapy, and immune checkpoint inhibitors. As such, NRF2 therapeutic inhibitors are actively being sought. We previously reported that the antiparasitic drug Pyrimethamine (PYR) inhibits NRF2 in cells and in an NRF2-inducible genetically engineered mouse model. Here we design, synthesize, and define structure-activity relationships across a series of 25 PYR-based derivatives to reveal WCDD115 as a 22-fold more potent inhibitor of NRF2 (57nM versus 1.2mM). PYR is known to inhibit plasmodial and human dihydrofolate reductase (DHFR). We found that WCDD115 inhibits hDHFR with 31-fold greater potency than PYR (144nM versus 4.49mM). Metabolomics showed strong similarities between PYR, WCDD115 and methotrexate. Genetic, pharmacological and metabolic epistasis studies reveal that DHFR inactivation is required for NRF2 suppression by WCDD115 and PYR. Global and targeted proteomics revealed overlapping profiles for WCDD115, PYR and methotrexate, including suppression of NRF2 oxidative stress response and activation of TP53 and the DNA damage response. As such, PYR and its more potent derivative WCDD115 are effective, indirect inhibitors of NRF2 and its antioxidant functions. These data underscore the importance of one-carbon metabolism for the NRF2 signaling pathway and supports a new therapeutic strategy to suppress NRF2-driven cancer biology.

2025-10-13 | PXD059011 | Pride

Microarray Profiling of Messenger RNAs Associated with DHFR Knock-down and DHFR2 Knockout in HepG2 cell line

Project description:Dihydrofolate reductase activity is essential for the maintenance of One Carbon Metabolism, as it provides the pathway with tetrahydrofolate (the biologically active form of folate). Most of this cellular activity is due to DHFR. Its paralogue DHFR2 was thought to be responsible for mitochondrial dihydrofolate activity based on recombinant versions of the enzyme. However, the function of the endogenous gene/protein has yet to be assessed. This study aimed at investigating the effects of DHFR2 gene loss in HepG2 cells to help identify its function. Furthermore, the expression profile of the DHFR knockdown was interrogated to assess whether DHFR lowered expression has an impact on DHFR2.

2024-02-01 | E-MTAB-12958 | biostudies-arrayexpress

Project description:Laboratory evolution of dihydrofolate reductase (DHFR)

| PRJNA923701 | ENA

Methotrexate-based PROTACs as DHFR chemical probes

Project description:Methotrexate (MTX) is a potent inhibitor of dihydrofolate reductase (DHFR), where is it used as both an antineoplastic and an immunosuppressant. Mechanisms of MTX resistance in cancers include MTX polyglutamylation and upregulation of DHFR. A series of MTX-based PROteolysis TArgeting Chimeras (PROTACs) were designed to selectively degrade human DFHR. These on-target, cell-active PROTACs show proteosome- and E3 ligase-dependent DHFR degradation, selective degradation of DHFR by proteomics, and interpretable structure-activity relationships. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX, indicating these compounds can complement conventional DFHR enzymatic inhibitors as tool compounds. This chemical probe set, composed of the PROTAC (Diruotrexate), its ester pro-drug (Diruotrexate-ester) and negative control analogs (Diruotrexate-IA1, -IA2), should serve as useful tools for studying one-carbon biochemistry.

2025-05-06 | PXD030140 | Pride

Hard-wiring in the Plasmodium falciparum transcriptome 2

Project description:To help malaria parasites survive unpredictable host immune responses, it is known that genes for surface proteins express stochastically in Plasmodium falciparum. Here, we demonstrate that gene expression for intracellular metabolic functions may be preordained and insensitive to specific metabolic perturbations. In a tightly-controlled, large microarray study involving over 100 hybridizations to isogenic drug-sensitive and drug-resistant parasites, the lethal antifolate WR99210 failed to over-produce RNA for the biochemically and genetically proven target dihydrofolate reductase-thymidylate synthase (DHFR-TS). Beyond the target, this transcriptional obstinacy carried over to the rest of the parasite genome, including genes for target pathways of folate and pyrimidine metabolism. Even 12 hours after commitment to death, the transcriptome remained faithful to evolutionarily entrained paths. A system-wide transcriptional disregard for metabolic perturbations in malaria parasites may contribute to selective vulnerabilities of the parasite to lethal antimetabolites. While large protective metabolic responses were not detected, DNA microarrays helped capture small, but reproducible drug-dependent perturbations within hours of drug exposure. In addition, in Plasmodium cells that had adapted to long-term drug exposure, DNA microarrays revealed new, large genome-wide transcriptional adjustments in the hard-wired transcriptional program itself. Keywords: Plasmodium falciparum treated with pyrimethamine RNA from pyrimethamine-treated parasite vs RNA from untreated control, Pyr-sensitive TM4/8.2 strain, pyrimethamine concentration at IC50 and treated for 0 h and 24 h, microarray data were obtained from at least four hybridizations using RNA from at lease two independent parasite cultures

2010-05-16 | E-GEOD-9853 | biostudies-arrayexpress

Hard-wiring in the Plasmodium falciparum transcriptome II

Project description:To help malaria parasites survive unpredictable host immune responses, it is known that genes for surface proteins express stochastically in Plasmodium falciparum. Here, we demonstrate that gene expression for intracellular metabolic functions may be preordained and insensitive to specific metabolic perturbations. In a tightly-controlled, large microarray study involving over 100 hybridizations to isogenic drug-sensitive and drug-resistant parasites, the lethal antifolate WR99210 failed to over-produce RNA for the biochemically and genetically proven target dihydrofolate reductase-thymidylate synthase (DHFR-TS). Beyond the target, this transcriptional obstinacy carried over to the rest of the parasite genome, including genes for target pathways of folate and pyrimidine metabolism. Even 12 hours after commitment to death, the transcriptome remained faithful to evolutionarily entrained paths. A system-wide transcriptional disregard for metabolic perturbations in malaria parasites may contribute to selective vulnerabilities of the parasite to lethal antimetabolites. While large protective metabolic responses were not detected, DNA microarrays helped capture small, but reproducible drug-dependent perturbations within hours of drug exposure. In addition, in Plasmodium cells that had adapted to long-term drug exposure, DNA microarrays revealed new, large genome-wide transcriptional adjustments in the hard-wired transcriptional program itself. Keywords: Plasmodium falciparum treated with pyrimethamine RNA from pyrimethamine-treated parasite vs RNA from untreated control, Pyr-sensitive TM4/8.2 parasite strain, pyrimethamine concentration at IC50 and treated for 2 h, 4 h, and 8 h, microarray data were obtained from at least four hybridizations using RNA from at least two independent parasite cultures

2010-05-16 | E-GEOD-9868 | biostudies-arrayexpress

To investigate the effects of NRF2 inhibitors (pyrimethamine) on mRNA expression in mouse esophageal epithelium.

Project description:To study the effects of NRF2 inhibitors (pyrimethamine) on mRNA expression in mouse esophageal epithelium.

2023-10-12 | GSE235584 | GEO

To investigate the effects of NRF2 inhibitors (pyrimethamine and mitoxantrone) on gene expression in a human esophageal squamous cell carcinoma cell line (KYSE70)

Project description:To study the effects of NRF2 inhibitors (pyrimethamine or mitoxantrone) on human esophageal squamous cell carcinoma cells.

2024-04-22 | GSE173164 | GEO

To investigate the effects of NRF2 inhibitors (pyrimethamine and mitoxantrone) on mRNA expression in a human esophageal squamous cell carcinoma cell line (KYSE70 cells)

Project description:To study the effects of NRF2 inhibitors (pyrimethamine or mitoxantrone) on human esophageal squamous cell carcinoma cells.

2023-10-12 | GSE235587 | GEO

Expression Analysis of WR99210-treated Mycobacterium tuberculosis H37Rv

Project description:Investigation of whole genome gene expression level changes in Mycobacterium tuberculosis treated with the DHFR inhibitor WR99210, compared to untreated cells. The antimycobacterial properties of WR99210 are further described in Gerum, A., Ulmer, J., Jacobus, D., Jensen, N., Sherman, D., and C. Sibley. 2002. Novel Saccharomyces cerevisiae screen identifies WR99210 analogues that inhibit Mycobacterium tuberculosis dihydrofolate reductase. Antimicrob Agents Chemother 46(11):3362-3369 [PMID:12384337]

2012-09-18 | GSE40917 | GEO

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