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This study found the one change that always happened when prostate cancer became resistant to hormone-blocking drugs: the cell made more androgen receptor. With enough of it, the drugs that were meant to block the receptor started switching it on instead.
Charles Chen and colleagues in Charles Sawyers's laboratory profiled isogenic prostate cancer xenografts before and after they became resistant to antiandrogen therapy. Across the models, a modest increase in androgen receptor messenger RNA was the only change consistently associated with resistance, and it was both necessary and sufficient to convert hormone-sensitive growth into hormone-refractory growth.
The mechanistic half of the paper matters as much as the observation. At high receptor levels, antagonists behaved as agonists, and the switch tracked a change in which coactivators and corepressors were recruited to the promoters of androgen receptor target genes. That is the biology behind antiandrogen withdrawal response, and it is the design brief that produced enzalutamide, which came out of the same laboratory.
The design specification for the second-generation antiandrogens. A drug for castration-resistant prostate cancer has to stay an antagonist when the receptor is abundant, which is what enzalutamide, apalutamide and darolutamide were engineered to do and what bicalutamide fails to do.
A demonstration that a drug that has stopped working can be made to work again by changing the environment the tumour has adapted to, rather than by changing the drug. It is the strongest clinical evidence in prostate cancer for treating resistance as something reversible.
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.
An oral drug that works after chemotherapy has failed, in a disease where the previous option was more chemotherapy. Together with abiraterone it moved castration-resistant prostate cancer from a chemotherapy disease to a hormonal one, and set up the sequencing questions the field is still arguing about.
The proof, in people, that castration-resistant prostate cancer is usually still androgen-driven. It renamed the disease (hormone-refractory became castration-resistant) and it opened the line of drugs that now dominate treatment at every stage from first diagnosis of metastatic disease onwards.
The first evidence that resistance to hormone therapy in prostate cancer is an adaptation of the target rather than an escape from it, which is why the field kept building better androgen receptor drugs instead of abandoning the pathway.
Shares RESTORE: bipolar androgen therapy after progression on enzalutamide in metastatic castration-resistant prostate cancer, Bipolar androgen therapy (BAT), Take high-dose testosterone to phase 3, with progression-free survival through the second line as the primary endpoint, Enzalutamide and the tag prostate-evidence.
Shares In vivo amplification of the androgen receptor gene and progression of human 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.
Shares AFFIRM: increased survival with enzalutamide in prostate cancer after chemotherapy, Enzalutamide, 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 Charles L. Sawyers, 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 and the tag prostate-evidence.
Shares AFFIRM: increased survival with enzalutamide in prostate cancer after chemotherapy, 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, Acquired resistance to every therapy and the tag prostate-evidence.
Shares 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, Acquired resistance to every therapy, Metastatic castration-resistant prostate cancer and the tag prostate-evidence.
Shares AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, Bipolar androgen therapy (BAT), Enzalutamide, 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, 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.