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

SIMPLE SUMMARY: Biochemical inhibition of male sex hormone function (androgen signaling), also known as androgen deprivation therapy (ADT), for human prostate cancer remains a major treatment strategy almost 80 years after the discovery of androgens as a major factor in the disease. Drug development has resulted in an increasing potency, whereas the understanding of the consequences of these new-generation inhibitors in cancer survivors for increased periods of time, and indeed for their individual cancer cells, has lagged behind. Drugs are still tested in laboratory cell systems developed 40 years ago, which indicate a toxic effect of the antiandrogens on the tumor cells, not matched by direct studies of human tissues. In this review, I discuss the limits of our understanding of both how these drugs work and potential side effects, which are often overlooked in the face of a perceived urgency to get better inhibitors in to the clinic. 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.