Figure 2.
Model by which the treatment naïve prostate cancer (CaP) changes from complete androgen dependence to castration-resistant prostate cancer (CRPC). Treatment with 1st generation of anti-androgens kills a majority of wild-type, androgen receptor (AR)-expressing androgen sensitive cells. However, some of these cells acquire AR mutations, some express AR splice variants, and some trans-differentiate to cancer stem-like cells by expressing stemness genes. Second generation anti-androgens attacks only some of the mutated AR expressing cells; because of the plasticity of the CaP cells, some survive, repopulate heterogeneous cancer cells throughout the prostate, and there is cancer relapse. To target all mutated and splice variant AR positive-cells and cancer stem-like cells, total AR degradation together with inhibitors of stem-like cells will be necessary. Only this way will a lethal environment be created that will eradicate all CaP cells irrespective of their heterogeneity.