21P Polymerase theta inhibition in homologous recombination-deficient prostate cancer
Bibliographic record
Abstract
PARP inhibitors olaparib, niraparib, rucaparib are approved for treatment of mCRPC harboring Homologous Recombination Deficiency (HRD). However, not all patients who receive these therapies respond and many ultimately develop resistance. This study aims to identify new PARP alternative targetable pathways to improve outcomes of HRD Prostate Cancer (PCa) patients. PCa samples from TCGA were divided in 2 groups on the basis of HR genomic status (HRD and non-HRD) and further divided in POLQ high and POLQ low according to POLQ median gene expression. Human PCa cell lines (LNCaP, C42) were transfected with si-scr or si-POLQ. Cell viability was evaluated by colony formation assay. POLQ expression was evaluated by RT-PCR. Immune signatures were used to assess immune activation. Kaplan-Meier and logrank test were used to analyze Progression Free Survival (PFS). ANOVA and t-test were used for groups comparisons. GSEA of the TCGA dataset showed high activation of of translesion (TLS) DNA pathways in HRD PCa (p<0.05; FDR <0.25). Polymerase theta (Polθ encoded by POLQ gene) was the only TLS polymerase to have higher expression in HRD vs HRR samples (p=2.508e-4). POLQ expression was associated with higher TMB especially in the HRD subgroup (p<0.0001). PFS of was significantly shorter in the POLQ high patients compared to POLQ low patients, regardless the HRD status (p=1.037e-5). Si-POLQ significantly decreased LNCaP cells spheroid growth (p<0.0001). POLQ silencing also leaded to higher sensitivity to olaparib in both LNCaP and C42 cells (IC50: 6.38 vs 3.4 uM for LNCaP and 13.5 vs 7.7 uM in C42; p<0.05). Moreover, POLQ mRNA levels significantly increased in the olaparib resistant LNCaP and C42 cells (p<0.0001). POLQ-silencing was able to overcome olaparib resistance in LNCaP (IC50: 47.3 uM vs 26.46 uM; p<0.05). Immune activation signature was not significantly different in the HRD vs non-HRD PCa samples. However, POLQ was highly expressed in the HRD and immune hot PCa samples (p=4.637e-4). The HRD PCa samples with high POLQ expression demonstrated the highest immune scores (p<0.0001). Polθ is over expressed in HRD PCa and is associated with olaparib resistance and immune activation representing a potential therapeutic target for HRD PCa patients.
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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) | 0.001 | 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".