Loading
The p53 and RB checkpoints are the cell's brakes. p53 senses damage and stops the cell from copying itself; RB holds the cell at the G1 gate until CDK4/6 unlocks it. Cancers cut these brakes.
DNA damage activates ATM/ATR → CHK2/CHK1 → p53 stabilisation (MDM2 degrades p53 normally). p53 induces p21, which inhibits CDK4/6-cyclin D and CDK2-cyclin E, keeping RB bound to E2F and the cell in G1. Cyclin D1 amplification, CDK4 amplification, CDKN2A (p16) loss, RB loss, and TP53 mutation (50% of cancers) each release the brake. CDK4/6 inhibitors re-impose it in RB-intact HR+ breast cancer; WEE1 and PLK1 inhibitors exploit G2/M dependence in TP53-mutant cells; MDM2 inhibitors reactivate wild-type p53.
A checkpoint at a border: p53 is the inspector who halts traffic when something looks wrong, MDM2 is the manager who keeps sending the inspector home, RB is the barrier arm, and CDK4/6 is the motor that lifts it. Cancers bribe the inspector (TP53 mutation) or hot-wire the motor (cyclin D amplification).
It splits the alterations into two groups with different practical meanings. The repair defects are present at diagnosis at close to their castration-resistant prevalence, so testing early is worthwhile; AR, TP53 and RB1 changes accumulate later, so a diagnostic sample does not answer questions about the disease in front of you at relapse.
It fills the gap between the primary-tumour atlases and the castration-resistant series by describing the disease at the moment most treatment decisions are actually made, and it identifies SPOP as a favourable marker rather than a neutral one.
It is the most disciplined outcome analysis in this disease and its result is deflationary in a useful way: most of the alterations people quote as prognostic do not survive adjustment, and the one that does, RB1, is also the one that marks the route to neuroendocrine transformation.
The driver count is a prognostic score in itself, and the allele matters: G12D is the pancreatic allele with the worst outlook and the one the new selective inhibitors chase.
It shows that the useful information in a castration-resistant plasma sample is in the repair genes and TP53 rather than in the androgen receptor finding that dominates the report, and it is the closest thing the field has to a head-to-head comparison of abiraterone against enzalutamide.
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.
It validates a clinical definition against a molecular one, which is unusual and useful: a man whose disease behaves like small cell carcinoma can be treated as such even when his biopsy does not look like it, because the underlying genotype is the same.
Why small-cell lung cancer has no targeted therapy in the conventional sense: it is built from the loss of TP53 and RB1, and the drugs that transformed non-small-cell disease inhibit gains rather than restore losses. The NOTCH result pointed at DLL3 and, eventually, at tarlatamab.
Shares Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma, Cellular senescence, Chronic myeloid leukaemia (KEGG map), Melanoma (KEGG map).
Shares Comprehensive molecular portraits of human breast tumours, MicroRNAs in cancer, Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers, Genomics of lethal prostate cancer at diagnosis and castration resistance.
Shares Circadian control, Basal cell carcinoma (KEGG map), MicroRNAs in cancer, Bladder cancer (KEGG map).
Shares Hallmark: evading growth suppressors, Oncogenic genomic alterations, clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer, Endometrial cancer (KEGG map), Thyroid cancer (KEGG map).
Shares Circadian control, Basal cell carcinoma (KEGG map), Endometrial cancer (KEGG map), Melanoma (KEGG map).
Shares Milestone prizes for first-in-class mechanisms reaching human proof of concept, Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma, An open-science consortium on the undruggable drivers, open until a candidate, MicroRNAs in cancer.
Shares Apoptosis, MicroRNAs in cancer, Cellular senescence, Small cell lung cancer (KEGG map).
Shares Comprehensive molecular portraits of human breast tumours, Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers, Genomics of lethal prostate cancer at diagnosis and castration resistance, Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance.