# Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance

Source: https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/  
OnCo record `paper-ku-rb1-trp53-lineage-plasticity-science-2017` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Deleting two tumour suppressor genes in mouse prostate cancer let the tumour change cell type, spread, and shrug off hormone treatment, and a drug that resets the chromatin reversed it.

## Summary

Studying mouse models, the authors showed that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation, and that additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicated that the mouse tumours resemble human prostate cancer neuroendocrine variants, and both mouse and human tumours showed increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant EZH2 inhibitors restored androgen receptor expression and sensitivity to antiandrogen therapy.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Science
- Year: 2017
- DOI: 10.1126/science.aah4199
- Authors: Ku SY, Rosario S, Wang Y, et al.
- Findings: Rb1 loss enables lineage plasticity and metastasis in Pten-mutant prostate adenocarcinoma.; Additional Trp53 loss causes antiandrogen resistance.; Increased Ezh2 and Sox2 expression in both mouse and human neuroendocrine-like tumours.; EZH2 inhibition restored androgen receptor expression and antiandrogen sensitivity.
- What it means: It turned neuroendocrine transformation from a pathological curiosity into a mechanism with a genotype and a candidate intervention, and it is the reason EZH2 inhibitors are in prostate cancer trials at all.
- Caveats: Genetically engineered mouse models, and the human confirmation is correlative.; EZH2 inhibition has not yet been shown to prevent or reverse transformation in men.; Loss of RB1 and TP53 is necessary but clearly not sufficient, since most such tumours do not transform.

## Sources

- Ku et al., Science 2017: Rb1 and Trp53 loss cooperating to allow lineage plasticity, metastasis and antiandrogen resistance in mouse prostate cancer: https://doi.org/10.1126/science.aah4199
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28059767/
- Europe PMC: https://europepmc.org/article/MED/28059767

## Connected records

- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- key papers: [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/)
- ideas: [Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it](https://onco.cc/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/)
- pathways: [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [EZH2](https://onco.cc/targets/ezh2/), [PTEN](https://onco.cc/targets/pten/), [RB1](https://onco.cc/targets/rb1/), [SOX2](https://onco.cc/targets/sox2/), [TP53](https://onco.cc/targets/tp53/)
- terms: [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/)
- journals: [Science](https://onco.cc/journals/science/)
- biomarkers: [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)

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