Figure 9.

Models for development of castration-resistant prostate cancers. Upper Panel: In a trans- or dedifferentiation model of resistance, the tumor cells are growth arrested by the presence of the AR inhibition. During growth arrest, the tumor cells have a genetic plasticity which pushes tumor cells towards a drug-resistant phenotype by the presence of the drug. Most tumor cells can therefore be the progenitors for the resistant (CRPC) tumor, and the CRPC cells will share most if not all of the mutations in the original bulk tumor cells. Lower Panel: In a hierarchical or stem cell model of resistance, there is a small population of relatively undifferentiated (or stem-like) cells present in every tumor, which contain cancer driver mutations. Under selective pressure from an anti-AR drug, which arrests the growth of the bulk cancer cells, variants can emerge from the common pre-existing precursor which develop new adaptive mutations. Assuming that the original bulk cancers had developed adaptive mutations from their underlying progenitors, the resultant CRPC cells should share only the driver mutations with the original cancers and have a new set of changes for growth under ADT conditions.