Abstract PO-053: Chemical suppression of DHFR induces NRF2 inhibition and tumor regression
Bibliographic record
Abstract
Abstract Background: Recurrence in head and neck squamous cell carcinoma (HNSCC) is common due to primary resistance and acquired resistance arising during therapy. Recent studies have highlighted a critical role of NRF2 in radiation (RT) resistance. Constitutive activation of the NRF2 oxidative stress response pathway occurs in 20-30% of primary HNSCC. As a ROS-activated transcription factor that is frequently mutated and active in cancer, NRF2 is central to both intrinsic and acquired determinants of RT resistance. We recently showed that high NRF2 activity is predictive for locoregional failure and poor outcomes following RT in HNSCC. The downstream effectors of NRF2 responsible for RT resistance are poorly defined. Therapeutic strategies to inhibit NRF2 may improve HNSCC patient outcomes, yet remain unproven. Methods: We sought to study NRF2 activation and biology in two model systems: MOC1 syngeneic HNSCC cells and mouse embryonic fibroblasts (MEFs) derived from a NRF2E79Q genetically engineered mouse model. We defined a transcriptional signature associated with an activating NRF2 mutation (NRF2E79Q) and characterized the effect of NRF2 on cell growth and RT response. We also investigated a novel NRF2 inhibitor in the syngeneic mouse MOC1 model. MEFs were isolated from a pregnant mouse, immortalized and selectively infected with 500-800 MOI of Adenovirus Cre-Recombinase for in vitro proliferation and RT assays. Drug studies were performed at 50mM in vitro or 20mg/kg PO daily starting day 7 in vivo. RT was delivered at 0, 4Gy, or 8Gy in vitro or 3Gy daily x 5 days starting day 17 in vivo. Results: RNA isolated from NRF2E79Q MEFs demonstrated activation of numerous oxidative stress pathway transcripts including canonical targets HMOX1, NQO1, BLVRB, and SLC71a11. NRF2E79Q MEFs demonstrated significantly enhanced baseline growth kinetics and RT resistance relative to the NRF2-wildtype line. We recently reported that pyrimethamine—an FDA-approved antiparasitic drug that targets one carbon metabolism— [1.2uM] induced NRF2 ubiquitylation and degradation in vitro and in vivo. Through structure-activity relationship optimization we have produced a novel analogue, [WCDD115; 50nM], with efficacious DHFR suppression and NRF2 inhibition in human and mouse HNSCC cell lines. In vitro, WCDD115 produced growth suppression in the MOC1 cell line which was enhanced in the setting of RT relative to either treatment alone. MOC1-bearing mice treated with WCDD115 or RT as monotherapy had significant reduction in growth kinetics relative to vehicle control. WCDD115 and RT combination therapy produced the greatest effect with significant growth suppression and 25% tumor rejection without weight loss or toxicity. Conclusions: Our study demonstrates that NRF2E79Q mutation is associated with enhanced growth kinetics and RT resistance along with upregulation of oxidative stress pathway targets. Drug targeting with the novel NRF2 inhibitor, WCDD115, has significant tumor suppressive activity in vitro and in vivo and warrants further investigation as a RT-sensitizing agent. Citation Format: Paul Zolkind, Harit Panda, Caroline Krall, Brittany Bowman, Nathan Wamsley, Bernard Weissman, Ben Major. Chemical suppression of DHFR induces NRF2 inhibition and tumor regression [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-053.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".