Abstract 1625: Redox homeostasis is a therapeutic vulnerability in lethal neuroendocrine prostate cancer
Bibliographic record
Abstract
Abstract Background: Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer that often develops after second-generation anti-androgen therapies. The current treatment options for NEPC are limited and only produce disappointing results, highlighting the urgent need for novel therapies. Previously, we have found that NEPC cells are vulnerable to BCL2 and GPX4 inhibitors compared to their counterparts, prostate adenocarcinoma (PADC). Here, we aim to determine whether and how combining BCL2 and GPX4 inhibitors would enable optimal therapeutic effects in NEPC. Methods: We conducted drug synergism analyses of BCL2 and GPX4 inhibitors using NEPC cell lines and determined their impacts on the major cell death pathways by performing rescuing experiments. To further determine the molecular mechanisms of BCL2 and GPX4 inhibitors-induced cell death in NEPC, we measured the intracellular reactive oxygen species (ROS) levels and tested the rescuing effects of various antioxidants and reducing agents on cell death. Finally, we determined the in vivo therapeutic efficacy of BCL2 and GPX4 inhibitors in an NCI-H660 cell line-derived xenograft (CDX) tumor model. Results: Our results demonstrate that the BCL2 inhibitor ABT-199 and GPX4 inhibitor C18 synergistically induced apoptosis in NEPC cell lines in a ROS-independent manner. Although N-acetylcysteine (NAC) rescued ABT-199 and C18 cotreatment-induced apoptosis, the CellROX Green assay revealed no significant changes in ROS levels in ABT-199 and C18-cotreated cells. Surprisingly, reducing agents including tris(2-carboxyethyl)phosphine (TCEP) and Dithiothreitol (DTT) strongly rescued cell death induced by ABT-199 and C18 cotreatment. Our findings therefore suggested that the cell-killing effects of ABT-199 and C18 were due to ROS-independent disruption of redox homeostasis. Lastly, our preclinical tumor study showed that the ABT-199 and C18 combinatorial therapy significantly suppressed the tumor growth of NEPC. Conclusions: Our study validated the combination of BCL2 and GPX4 inhibitors as a feasible approach for the treatment of NEPC and suggested that redox homeostasis is a therapeutic vulnerability in NEPC. Citation Format: Mu-En Wang, Wei-Ling Tu, Ji-Hoon Kim, Yi Lu, Alyssa Bawcom, Andrew J. Armstrong, Qianben Wang, Yuzhuo Wang, Jiaoti Huang, Ming Chen. Redox homeostasis is a therapeutic vulnerability in lethal 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 1625.
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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) | 0.002 | 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 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".