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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.
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.
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.
Shares SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer, Treatment-emergent neuroendocrine transformation (recognising it), Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it, Histologic transformation.
Shares Treatment-emergent neuroendocrine transformation (recognising it), Histologic transformation, PTEN, Neuroendocrine and small-cell prostate cancer.
Shares RB1, Lineage plasticity & neuroendocrine transformation, Androgen receptor signalling, Castration-resistant prostate cancer (CRPC).
Shares SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer, Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it, Histologic transformation, Neuroendocrine and small-cell prostate cancer.
Shares Histologic transformation, Neuroendocrine and small-cell prostate cancer, Lineage plasticity & neuroendocrine transformation, Androgen receptor signalling.
Shares Treatment-emergent neuroendocrine transformation (recognising it), Histologic transformation, Neuroendocrine and small-cell prostate cancer, Epigenetic reprogramming.
Shares Treatment-emergent neuroendocrine transformation (recognising it), Histologic transformation, Neuroendocrine and small-cell prostate cancer, Lineage plasticity & neuroendocrine transformation.
Shares Histologic transformation, Neuroendocrine and small-cell prostate cancer, Lineage plasticity & neuroendocrine transformation, Androgen receptor signalling.