Abstract 1723: Ferroptosis is a novel therapeutic target for RB1 deficient lethal prostate cancer
Bibliographic record
Abstract
Abstract Background: Although the development of next-generation antiandrogens has significantly extended the survival time of patients with metastatic castration-resistant prostate cancer (mCRPC), drug resistance inevitably developed over time. Therefore, the identification of novel therapeutic strategies targeting mCRPC is urgent. RB1 deficiency is a common genetic event and contributes to the development of therapy resistance and poor prognosis in prostate cancer. However, effective therapies against RB1-deficient lethal prostate cancer remain elusive. Here we determined how RB1 regulates the sensitivity of prostate cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, and whether we can exploit ferroptosis for the treatment of RB1 deficient lethal prostate cancer. Methods: To determine how RB1 regulates ferroptosis in prostate cancer, we generated RB1 stable knockdown prostate cancer cell lines using lentivirus-delivered shRNAs. We compared cellular sensitivity to ferroptosis and associated lipid peroxidation between control and RB1 stable knockdown prostate cancer cells. Using western blotting, qPCR, and ChIP analyses, we examined the regulation of ferroptosis by RB1. We also evaluated the therapeutic efficacy of ferroptosis inducers in cell-derived xenograft, patient-derived xenograft, and genetically engineered mouse models. Results: Our studies revealed that RB1 deficiency sensitizes prostate cancer cells to ferroptosis. Mechanistically, we found that the E2F family of transcription factors directly binds and activates the ACSL4 promoter and that RB1 inhibits ferroptosis by suppressing E2F-mediated ACSL4 transcriptional activation. More importantly, our preclinical studies demonstrated that induction of ferroptosis by JKE-1674, a recently discovered ferroptosis inducer, significantly blocks RB1 deficient prostate tumor growth and metastasis, and improves the overall survival of mice in the absence of obvious toxicity. Conclusions: Our findings uncover an RB1/E2F/ACSL4 molecular axis that governs ferroptosis and also suggest a new approach to the treatment of RB1-deficient lethal prostate cancer. Citation Format: Mu-En Wang, Jiaqi Chen, Yi Lu, Jinjin Wy, Jianhong Ou, John Asara, Andrew Armstrong, Qianben Wang, Lei Li, Yuzhuo Wang, Jiaoti Huang, Ming Chen. Ferroptosis is a novel therapeutic target for RB1 deficient lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1723.
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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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".