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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.
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.
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.
Biopsy of progressing lesions, especially with low PSA or visceral spread, is recommended to detect neuroendocrine transformation and switch to platinum-based therapy or trials.
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.
Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation.
The first predictive resistance biomarker in prostate cancer, and a mechanism rather than a correlation: a receptor with no ligand-binding domain cannot be blocked by a drug that binds the ligand-binding domain. It is also the origin of the case for androgen receptor degraders, which destroy the protein rather than blocking a site the protein no longer has.
Shares Charles L. Sawyers, AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, Androgen receptor signalling, Castration-resistant prostate cancer (CRPC) and the tag prostate-evidence.
Shares Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), Tumour heterogeneity and clonal evolution, Drug resistance (primary and acquired) and the tag prostate-evidence.
Shares Castration-resistant prostate cancer (CRPC), The undruggable drivers, 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, Androgen receptor and the tag prostate-evidence.
Shares Androgen receptor signalling, Epigenetic reprogramming, Castration-resistant prostate cancer (CRPC), Tumour heterogeneity and clonal evolution and the tag prostate-evidence.
Shares Tumour heterogeneity and clonal evolution, 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, Androgen receptor, Acquired resistance to every therapy and the tag prostate-evidence.
Shares Charles L. Sawyers, Androgen receptor signalling, Tumour heterogeneity and clonal evolution, 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 and the tag prostate-evidence.
Shares Charles L. Sawyers, Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), 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 and the tag prostate-evidence.
Shares AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, Castration-resistant prostate cancer (CRPC), 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, Androgen receptor and the tag prostate-evidence.