Abstract B026: Screening non-small cell lung cancer patient-derived organoids with epigenetic probes reveals PRMT5 as an oncogenic target
Bibliographic record
Abstract
Abstract Lung cancer is the leading cause of cancer-related mortality. Detection of drug actionable genetic alterations has made the standard systemic therapy to a more personalized one including targeted therapy and immune checkpoint blockade. Despite the initial response, majority of patients develop resistance to treatment. Therefore, understanding the mechanisms of resistance as well as discovering novel cancer targets is necessary. Resistance to therapies can be associated with an existing clone of tumor cells with genetic alteration, or the emergence of cells with epigenetic changes overcoming the treatment-induced stress. Therefore, investigating the epigenetic aberrations that occur in tumor cells may reveal novel targetable markers that can be of great clinical significance. Methods: Organoid models established from non-small cell lung cancer (NSCLC) patient surgical resections and pleural effusion were dissociated into single cells and plated in matrigel-coated 384-well plate. A panel of 32 NSCLC organoid models were treated with a library of 41 epigenetic probes (1uM) and a DMSO control over a period of 8 days. Cell titre glo assay was performed to measure cell survival. Results: Arginine methyl transferase protein 5 (PRMT5) inhibited the cell growth of large proportion of the NSCLC organoid models. LLY-283 showed the most significant effect, with 50% of all organoid models (16/32) treated with LLY283 showing ≥50% reduction in cell viability. Further testing with multiple concentrations of several PRMT5 inhibitors revealed models with differential responses to PRMT5 inhibition. To investigate the differential gene expression changes induced by PRMT5 inhibition, we performed RNA-sequencing on three PRMT5 inhibitor sensitive and three resistant organoid models. Ongoing analyses aim at identifying differentially expressed genes in sensitive and resistant models in response to PRMT5 inhibition, and pathway enrichment analysis to determine the differential mechanisms of response to PRMT5 inhibition. Conclusion: Epigenetic drug screening on a large cohort of NSCLC organoid models reveals PRMT5 as potential novel therapeutic target in NSCLC. Further correlative analysis with transcriptomic changes induced by the PRMT5 inhibitors may reveal biomarkers of response. Citation Format: Khadija Jafarova, Quan Li, Nikolina Radulovich, Geoffrey Liu, Ming S Tsao. Screening non-small cell lung cancer patient-derived organoids with epigenetic probes reveals PRMT5 as an oncogenic target [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B026.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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".