Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

Abstract

It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms-those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa), the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.

Keywords: androgen independence; bet-hedging; intermittent androgen therapy; non-genetic heterogeneity; phenotypic plasticity; stochasticity.

Figure 1

Bacterial Persistence. (A) Biphasic time-kill curve in bacterial populations exposed to antibiotics: faster killing rate of sensitive cell (green dotted line) followed by a slower killing rate (red dotted line) of persisters. In contrast, the antibiotic-resistant population continues to grow in presence of antibiotic (blue curve). (B) (top) An isogenic population of antibiotic sensitive cells can give rise to persisters via non-genetic/phenotypic plasticity. These slow-cycling persisters survive in the antibiotic treatment and tend to resume growth and generate a new population identical to the original population upon antibiotic removal (bottom). Persisters and non-persisters can switch among one another; the switching rate can be influenced by external stress factors. (C) Non-genetic heterogeneity of a key regulator of persistence (say X) in an isogenic population may give rise to two (or more) subpopulations that may continue switching stochastically among themselves to maintain persisters.

Figure 2

Modes of therapeutic resistance in cancer cells. (A) Cancer cells may resist cytotoxic drugs due to genetic mutations either pre-existing (de novo) in different clones that together constitute the cancer cell population, or those acquired during expansion of the drug-resistant clone. (B) An isogenic or a clonal population may be able to survive therapeutic assaults due to stochastic cell-to-cell variability of a key player regulating the formation of persisters. Drug treatment may enhance this non-genetic heterogeneity due to responsive diversification and/or drug-induced cellular reprogramming. This non-genetic heterogeneity can survive addition of cytotoxic drug, however, it can also lead to different acquired mutations by drug-tolerant persisters (DTPs) that can then be inherited by DTP clones. Dotted black line indicates which cells are persisters (to the right of it) versus which are not (to the left of it). (C) Same as (B), but without any change in variation of the levels of X; instead, the mean levels of X change. Cells shown in one color represent identical genetic makeup.

Figure 3

Non-genetic heterogeneity in prostate cancer. (A) Androgen receptor (AR)/prostate-associated gene 4 (PAGE4)/activator protein-1 (AP-1) circuit can give rise to oscillations of AR activity in a cell that can dynamically vary its dependence on androgen. These oscillations need not be synchronized across the population. (B) These oscillations, together with any other mechanisms of persistence, may survive a continuous androgen deprivation therapy and eventually regrow the entire population leading to tumor relapse (dotted black curve). However, “drug holidays,” such as intermittent androgen deprivation or bipolar androgen therapy may convert persisters to drug-sensitive cells, thus always keeping the number of androgen-independent (resistant) cells in check (solid green curve).