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.

Keywords: androgen deprivation therapy: tumor resistance; androgens; model systems; prostate cancer.

Figure 1

The evolution of direct (nonsteroidal) inhibitors of the androgen receptor. The increase in affinity of the drugs for the receptor with structural engineering is striking [4]. Note also that darolutamide is stated not to cross the blood–brain barrier, unlike the other molecules, and ralaniten binds to a different part (the flexible portion of the Androgen Receptor (AR) molecule, so a comparable IC50 is not appropriate. Ralaniten has recently been withdrawn due to low clinical efficacy, despite promising preclinical data).

Figure 2

The androgen signaling cascade in prostate epithelial cells.

Figure 3

Known therapeutic interventions to block androgen signaling. Specific inhibitors shown in red. Blue boxes correspond to headline strategies in Table 1. HSP: Heat Shock Proteins, LHRH: Luteinizing hormone-releasing hormone, Cyp17: Cytochrome P450 17α−hydroxy/17,20-lyase, AR: Androgen Receptor, PSA: Prostate Specific Antigen, DHT: Dihydrotestosterone, CRPC: Castration Resistant Prostate Cancer.

Figure 4

Alternative growth factor driven signaling pathways after androgen blockade. Canonical androgen response is shown on the right of the figure (as in Figure 3), whereas under conditions of limiting androgens or ADT, at least three alternative pathways can be activated, all resulting in steroid-independent activation of AR signaling: (i) Epidermal Growth Factor and Insulin-Like Growth Factor (EGF/IGF) stimulated signalling via Phosphatidylinositol 3-kinase (PI3K), Protein kinase B ( Akt/PKB) and mediated by phosphatidylinositol 3,4,5-triphosphate (PIP3) and Phosphatase and tensin homolog (PTEN) levels in cells. (ii) Signalling with the ras proto-oncogene (ras signalling) via Activated Cdc42-associated kinase (Ack), The Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK) pathway and the Proto-oncogene tyrosine-protein kinase Src (Src), and (iii) Interleukin 6 (IL6) cytokine signalling which activartes AR via janus kinase-signal transducer and activator of transcription (JAK1), signal transducer and activator of transcription 3 (STAT3) and histone acetyltransferase p300 (p300) intermediates as shown.

Figure 5

Gene expression studies after androgen blockade in prostate tissues. The total numbers of up and downregulated genes after ADT are shown in green and red, respectively, in Table 2.

Figure 6

Theoretical pathway inhibition after direct blockage of AR activity. Whilst most clinical emphasis is on the downstream effects (biomarkers such as PSA) of AR inhibition (B), the accumulation of signaling molecules before the blockade can have profound metabolic consequences (C). This is achieved not only by accumulation before the drug blockade, but also by feedback stimulation of flow into the pathway (D). Ultimately, the excess of substrate can be relieved in the cell by activation of a salvage pathway (E), which results in a restoration of output (PSA) by other means.

Figure 7

Accumulation of steroid precursors after inhibition of CYP17 by abiraterone. DHT: Dihydroteststerone, DHEA: dehydroepiandrosterone, ACTH: Adrenocorticotropic hormone.

Figure 8

Prior treatment with ADT in a human clinical trial does not induce resistance. In a human clinical trial [168], the results were best explained by a selection for pre-existing resistant cells, rather than induction by the presence of the AR inhibitor (IT = Immediate Therapy; DT = Delayed Therapy).

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.

Figure 10

Expression patterns of human androgen receptor in multiple and non-prostatic tissue data from Dart et al. [178] and other sources in text.