PRMT1 inhibitor MS023 suppresses RNA splicing to sensitize small cell lung cancer to DNA damaging agents
Bibliographic record
Abstract
Small cell lung cancer (SCLC) is a highly aggressive form of cancer, commonly treated with DNA-damaging therapies such as chemotherapy and radiotherapy. Unfortunately, relapse occurs early and frequently, suggesting that epigenetic mechanisms may play a role in this aggressive behavior. Targeting these mechanisms during initial treatment could potentially enhance anti-cancer effects. This study investigated the combination of DNA-damaging treatments with a panel of Epigenetic Chemical Probes (EpiProbes). Among these, MS023, a PRMT inhibitor, showed the greatest synergy with cisplatin and etoposide across various SCLC cell lines. The cytotoxicity of MS023 was correlated with PRMT1 gene expression and protein levels. BioID analysis revealed that many PRMT1 interactors are involved in mRNA splicing. Mechanistic validation demonstrated that MS023 impaired RNA splicing, increased DNA:RNA hybrids, and caused DNA double-strand breaks (DSBs). When combined with ionizing radiation (IR), MS023 significantly increased DSBs, as indicated by γH2AX foci. Additionally, MS023 enhanced the effects of IR and the PARP inhibitor talazoparib, both in vitro and in vivo. Therefore, targeting PRMT1 in combination with DNA-damaging therapies presents a promising strategy to improve treatment outcomes for SCLC.
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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) | 0.000 | 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 | 0.000 |
| 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".