Abstract 4748: Understanding the RSAD2/CMPK2 signaling axis in PVT1 exon 9 overexpressed neuroendocrine prostate cancer
Bibliographic record
Abstract
Introduction/Background: Plasmacytoma variant translocation 1 (PVT1) is overexpressed in prostate cancer (PCa) and alters gene expression directly or by acting as a noncoding RNA sponge. Our group previously identified overexpression of PVT1 exon 9 in aggressive PCa tissues and cell lines and overexpression led to transformation of non-tumorigenic prostate epithelial cells to PCa with neuroendocrine prostate cancer (NEPC) phenotype when implanted in vivo. RNA-sequencing analysis of our PVT1 exon 9 overexpression PCa model revealed upregulation of Radical S-Adenosyl Methionine Domain Containing (RSAD2) downstream of PVT1 exon 9. We have uncovered RSAD2 overexpression as a common characteristic of NEPC and have elucidated two novel molecular pathways at play in this disease; PVT1 exon 9 independent and dependent RSAD2 upregulation. These pathways lead to differences in Type II interferon signaling, immune signaling and AR sensitization. RSAD2 is located upstream of and directly interacts with CMPK2 in a variety of cellular models and some of their functions are interdependent. Objectives/Hypothesis: We hypothesize that RSAD2 and CMPK2 work together to contribute to NEPC pathogenesis regardless of PVT1 exon 9 overexpression status. Methods: We tested this hypothesis with a variety of genetic and biochemical approaches. Results: RNA-sequencing analysis of our PVT1 exon 9 overexpression NEPC model (RWPE1, RWPE1_ev, RWPE1_ex9) revealed significant (p-value < 0.05) upregulation of RSAD2 and CMPK2, in RWPE1_ex9 as compared to RWPE1_ev and RWPE1. In a second NEPC model (that also models circulating tumor cells in metastasis) derived from 22RV1 castrate-resistant prostate cancer (CRPC) parental cells implanted in vivo and isolated from blood, we found overexpression of PVT1 exon 9, RSAD2 and CMPK2 in isolated circulating tumor cells (C22OH) we have previously validated as having neuroendocrine features. In NEPC models that do not overexpress PVT1 exon 9, such as DU145 and NCI-H660, we found only overexpression of RSAD2 but not CMPK2. Knockdown of CMPK2 led to ∼35% decreased cell viability in all models suggesting that CMPK2 may be a cancer promoting aberration in NEPC. Both RSAD2 and CMPK2 are clinically relevant and significantly overexpressed in neuroendocrine prostate cancer human cohorts. Overexpression models of CMPK2 revealed alterations in cell proliferation, colony formation and PD-L1 immune signaling and localization suggestive of a larger role in prostate cancer pathogenesis. Discussion/Conclusions: Based on these results, PVT1 exon 9, RSAD2 and CMPK2 are promising therapeutic targets in PVT1 exon 9 overexpressed NEPC whereas RSAD2 targeting alone may be more useful in NEPC without PVT1 exon 9 overexpression. Further investigation is ongoing to understand therapeutic strategies to use alone or in combination with current clinically approved therapeutics. Citation Format: Rachel E. Bonacci, Meghan McGill, Nu Thuy Anh Le, Murtaza Barkarar, Chinedum Udekwu, Olorunseun O. Ogunwobi. Understanding the RSAD2/CMPK2 signaling axis in PVT1 exon 9 overexpressed neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4748.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".