Resistance to Antiandrogens in Prostate Cancer: Is It Inevitable, Intrinsic or Induced?

Abstract

Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even the most sophisticated drug regimes, and both tumor cell heterogeneity in prostate cancer and the multiple salvage pathways result in castration-resistant disease related genetically to the original hormone-naive cancer. The timing and mechanisms of cell death after ADT for prostate cancer are not well understood, and off-target effects after long-term ADT due to functional extra-prostatic expression of the androgen receptor protein are now increasingly being recorded. Our knowledge of how these widely used treatments fail at a biological level in patients is deficient. In this review, I will discuss whether there are pre-existing drug-resistant cells in a tumor mass, or whether resistance is induced/selected by the ADT. Equally, what is the cell of origin of this resistance, and does it differ from the treatment-naïve tumor cells by differentiation or dedifferentiation? Conflicting evidence also emerges from studies in the range of biological systems and species employed to answer this key question. It is only by improving our understanding of this aspect of treatment and not simply devising another new means of androgen inhibition that we can improve patient outcomes.

Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse

“…As differentiating between benign basal epithelia and tumor epithelia remains one of the major questions of the PC field, understanding the presence and function of these persistent and potentially regenerative cells in histopathologically noncancerous regions warrants further studies. Our data show evidence of a hierarchical model of emergence of enzalutamide resistance 41 in which treatment-persistent cells are able to regenerate the bulk of resistant cells. We describe the properties of the persistent cells using RNA velocity and show different intermediate states in alternative trajectories of treatment resistance.…”

MicroRNAs as Epigenetic Determinants of Treatment Response and Potential Therapeutic Targets in Prostate Cancer

“…In the last decade, miRNAs emerged as crucial molecular regulators of several cellular pathways involved in PCa response and development of resistance to hormone therapy and chemotherapy. As regards ADT, the resistant phenotype has been frequently associated with the reactivation of AR signaling or the overcoming of androgen dependence by hiring additional cell survival pathways independent from AR functional activation [ 121 ].…”

Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing

“…Abiraterone, a relatively novel agent, can block intratumoral testosterone production, but PCa cells have various routes of resistance. For example, gain-in-function mutations in the AR allow it to use other molecules as ligands, such as those downstream of glucocorticoid or IL-6 transmembrane signaling, in order to translocate into the nucleus and cause gene expression [ 23 ]. Enzalutamide, one of the strongest anti-androgen agents, can block AR’s promiscuity with other molecules; however, PCa cells are resilient and eventually continue proliferating, even in the absence of AR activity.…”