Abstract IA-016: Metabolic deregulation drives a redox vulnerability in pancreatic cancer
Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is an almost universally fatal malignancy and there is an urgent need for new therapeutic targets. PDAC cells harbor genetic alterations and display metabolic changes that render them vulnerable to perturbations in redox homeostasis. Peroxiredoxin 4 (PRDX4) supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER). Based on functional genomics, we found that PDAC cell lines are dependent on PRDX4 for their growth and survival. We validated this dependency in established and primary PDAC cells, as well as in 3D models and orthotopic xenografts. PRDX4 depletion led to increased levels of reactive oxygen species (ROS). Tumor cells are exposed to fluctuating oxygen levels, which are known to augment ROS production. In line with this, PRDX4 addiction was also exacerbated in cells exposed to hypoxia and reoxygenation. Cell death induced by PRDX4 depletion was accompanied by DNA damage and a DNA-PKcs-governed DNA damage response. As such, PRDX4 depletion also sensitized cells and tumors to ionizing radiation. The source of ROS that created a dependency on PRDX4 was attributed to NADPH oxidase 4 (NOX4), which localizes to the ER membrane. The functional requirement for PRDX4 was correlated with cellular NADPH levels across different models of PDAC and could be rescued by depletion of NOX4 or NADPH. As such, this study has identified NOX4 as a link between metabolic deregulation and ER-specific redox vulnerability in PDAC. Since PRDX4 is not an essential gene in normal tissues, our work also suggests that PRDX4 represents a novel therapeutic target for pancreatic cancer that may be particularly potent in combination with radiotherapy. Citation Format: Marianne Koritzinsky, Pallavi Jain, Anna Dvorkin-Gheva, Lucie Malbeteau, Piriththiv Dhavarasa, Kevin R. Brown, Gun Ho Jang, Parth Vora, Faiyaz Notta, Jason Moffat, Paul C. Boutros. Metabolic deregulation drives a redox vulnerability in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-016.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| 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) | 0.001 | 0.000 |
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 teacher head, 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".