# SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer

Source: https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/  
OnCo record `paper-mu-sox2-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

Some prostate cancers escape hormone drugs not by changing the receptor but by becoming a different kind of cell that does not need it. This paper showed how: losing two tumour suppressors lets the cell switch on SOX2 and change identity, and restoring them reverses it.

## Summary

Ping Mu, Charles Sawyers and colleagues used human prostate cancer models in vitro and in vivo to show that tumours can develop resistance to enzalutamide by a phenotypic shift from androgen receptor-dependent luminal epithelial cells to androgen receptor-independent basal-like cells.

The chain is specific and, unusually, reversible. Loss of TP53 and RB1 function enables the plasticity; increased expression of the reprogramming transcription factor SOX2 mediates it; restoring TP53 and RB1 function or inhibiting SOX2 reverses it. Published back to back with Ku and colleagues in the same issue of Science, it supplies the mechanism behind the clinical observation that treatment-emergent small-cell neuroendocrine prostate cancer appears in men treated hard with androgen receptor drugs, and it says that the enabling lesions are detectable before the switch happens.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Also known as: Mu 2017; SOX2 lineage plasticity prostate; enzalutamide resistance by lineage switching
- Tags: prostate-evidence
- Journal: Science
- Year: 2017
- DOI: 10.1126/science.aah4307
- Authors: Mu P, Zhang Z, Benelli M, et al.
- Findings: Human prostate cancer models developed resistance to enzalutamide by a phenotypic shift from androgen receptor-dependent luminal epithelial cells to androgen receptor-independent basal-like cells.; The lineage plasticity is enabled by the loss of TP53 and RB1 function.; It is mediated by increased expression of the reprogramming transcription factor SOX2.; It can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression.; Mutations in tumour suppressor genes can therefore create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
- What it means: A mechanism for the most feared form of treatment resistance in prostate cancer, and the reason combined TP53 and RB1 loss is worth knowing about before a man starts an androgen receptor drug rather than after his biopsy comes back neuroendocrine. Reversibility in the laboratory is also an argument that the switch is a target and not just a prognosis.
- Caveats: Cell line and mouse models; no drug that restores TP53 or RB1 function or inhibits SOX2 exists for patients.; Combined TP53 and RB1 loss is necessary but not sufficient in these models, and most men with both lesions do not develop neuroendocrine disease.; The clinical frequency of lineage switching is measured elsewhere: Aggarwal and colleagues found treatment-emergent small-cell neuroendocrine carcinoma in 17 percent of metastatic biopsies in their cohort (paper-aggarwal-t-sccpc-jco-2018).

## Sources

- Science 2017: https://doi.org/10.1126/science.aah4307
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28059768/

## Connected records

- key papers: [AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer](https://onco.cc/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/), [Clinical and genomic characterisation of treatment-emergent small-cell neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-aggarwal-t-sccpc-jco-2018/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers](https://onco.cc/key-papers/paper-rubin-mol-cell/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/)
- ideas: [Detect tumours changing cell type from RNA in the blood](https://onco.cc/ideas/idea-bio1-cfrna-plasticity-tracking/), [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/)
- 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/)
- 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/)
- fronts: [Epigenetic & Transcriptional Therapy](https://onco.cc/fronts/epigenetics/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [RB1](https://onco.cc/targets/rb1/), [SOX2](https://onco.cc/targets/sox2/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/), [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/)
- 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/), [Neuroendocrine differentiation in prostate cancer](https://onco.cc/terms/neuroendocrine-differentiation/)
- people: [Charles L. Sawyers](https://onco.cc/people/charles-sawyers/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [Science](https://onco.cc/journals/science/)
- biomarkers: [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)

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