In summary, by integrating high-content single-cell level imaging analyses with mechanistic studies, extensive preclinical therapeutic experiments and a Phase Ib clinical trial, our studies herein elucidate the AR<sup>+/-</sup>BCL-2<sup>+/-</sup> PCa cell subpopulation dynamics and credentials BCL-2 as a vital therapeutic target in heterogeneous CRPC. Here, BCL2 is linked to posterior cortical atrophy.