Is the Achilles' heel for prostate cancer therapy a gain of function in androgen receptor signaling?

Multiple genetic changes are required to produce prostatic cancer cells that can metastasize and kill the patient (1, 2). The most fundamental consequence of these molecular abnormalities is that the rate of malignant prostate cell proliferation exceeds its rate of cell death (3). It is this disruption of cellular homeostasis that results in the continuous net growth producing the lethality of this devastating disease. Successful therapy for the 30,000 U.S. males dying of prostate cancer annually will require approaches that shift the cell kinetic balance such that the rate of prostatic cancer cell death exceeds cell proliferation without producing unacceptable host toxicity. To have a realistic chance of developing such successful therapy, identification of the molecular changes driving the imbalance in proliferation vs. death of malignant prostate cells is critical. Androgens are the major growth factors for the normal prostate, and its cognate receptor is fundamental for androgen signaling within the gland (4). Prostate cancers retain androgen receptor (AR) signaling pathways and thus are nearly universally responsive initially to androgen ablation therapy. Unfortunately, however, essentially all ablated patients eventually relapse. Because of this relapse, androgen ablation therapy is not curative, no matter how complete the ablation (5). A growing body of data has documented that this is due to the accumulation of molecular changes inducing gain of function in the AR signaling pathways during the progression of prostatic cancer. These gain of function changes result in prostate cancer cells that are resistant to androgen ablation because of their acquired ability to activate novel AR signaling pathways for their proliferation and survival without requiring physiological androgen ligand binding. These changes produce malignancy unique signaling pathways that, while androgen ligand-independent, are still dependent upon AR, and this provides a therapeutic Achilles’ heel for control of this devastating disease. The rationale for this statement is based on the following facts. First, the AR gene is located on the X chromosome, and thus males have only a single copy of this gene. Second, germline truncation mutations early in the first exon of the AR gene result in complete androgen insensitivity syndrome because no expression of AR protein occurs in these patients (6). Although such complete androgen insensitivity syndrome mutations prevent masculinization, they are not life threatening (6). This means that in prostate cancer patients with germline wild-type AR, systemic therapy that either selectively prevents AR expression or neutralizes its signaling ability should not be lethal to normal host tissues, except the male accessory sex tissues. These accessory sex tissues undergo regression by standard androgen ablation without affecting host survival. Therefore, such systemic AR-targeted therapy would have a unique AR-dependent therapeutic index because blocking AR signaling while eliminating the metastatic prostate cancer cells remaining after androgen ablation would not be life threatening. Thus, prostate cancers should provide a paradigm for successful rational drug development based on this unique therapeutic index. For such rational drug development to take advantage of the Achilles’ heel of prostate cancer, identification of the novel malignancy-acquired constitutive AR signaling pathways is critical. As a background for such research, this review will focus on what is presently understood concerning the mechanism for androgen regulation of normal cellular homeostasis in the prostate and the genetic changes responsible for gain of function in the AR-signaling pathways acquired during prostatic carcinogenesis and progression.