NUAK2 is a therapeutically tractable regulator of RNA splicing and tumor progression in neuroendocrine prostate cancer
Bibliographic record
Abstract
Prostate cancer remains a leading cause of cancer-related mortality in men, with aggressive, treatment-emergent androgen receptor (AR)-indifferent subtypes, including double-negative prostate cancer (DNPC) and neuroendocrine prostate cancer (NEPC), posing major clinical challenges due to limited therapeutic options. NUAK family kinase 2 (NUAK2), an AMPK-related kinase, has been implicated in tumor growth and metastatic progression; however, its functional significance and therapeutic potential in advanced prostate cancer remain largely unexplored. Here, we identify NUAK2 as a therapeutically actionable kinase dependency in AR-indifferent prostate cancer. Transcriptomic analyses across independent patient cohorts demonstrated progressive upregulation of NUAK2 with disease progression, with the highest expression in NEPC. Immunohistochemical analysis of clinical specimens further confirmed elevated NUAK2 protein expression in NEPC relative to prostate adenocarcinoma. Genetic loss- and gain-of-function studies established NUAK2 as a functional dependency that promotes tumor cell proliferation, clonogenic growth, and tumor growth in vivo. Mechanistically, integrated proteomic analyses revealed that NUAK2 associates with spliceosomal and RNA-processing machinery, while NUAK2 perturbation induced widespread alterations in pre-mRNA splicing programs involving genes linked to mitotic regulation and oncogenic signaling. Pharmacologic studies identified trilaciclib (G1T-28), a clinically approved CDK4/6 inhibitor, as a functionally relevant NUAK2 inhibitor that directly engages NUAK2, suppresses tumor growth, and enhances the efficacy of platinum-based chemotherapy across multiple preclinical models. Collectively, these findings uncover NUAK2 as a previously unrecognized regulator of RNA splicing and therapeutic vulnerability in AR-indifferent prostate cancer and provide a rationale for repurposing G1T-28 and developing NUAK2-directed therapeutic strategies for aggressive, treatment-refractory prostate cancer.
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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) | 0.005 | 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".