Carcinomas of the prostate are the most common cancers affecting men and a leading cause of male cancer deaths in the United States (CDC web site, Cancer Prevention and Control). Given the unique association of the prostate with males, it makes sense that prosate carcinoma cells are often dependent for continued growth and proliferation on signaling by the androgen receptor, as andogens are primarily associated with physiological effects critical for male sexual development. Therefore, therapies aimed at inhibiting either androgen synthesis or androgen receptor function make great sense. In a recent paper by Chen et al. (2014), Steven Balk and colleagues demonstrate that treatment of castration-resistant prostate cancer with a drug (abiraterone) that inhibits the production of androgens can select for mutant androgen receptors (AR) that more effectively recognize and get activated by a non-androgen.
Abiraterone is an inhibitor of the enzyme cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1). This enzyme can transform 17-alpha-hydroxypregnenolone into the weak androgen dehydroepiandrosterone (DHEA). Other enzymes can then convert DHEA to more potent androgens such as testosterone and dihydrotestrosterone. Treatment of patients afflicted by castration-resistant prostate cancers with abiraterone decreases levels of downstream steroids, i.e. androgens, but may increase levels of progesterone and related steroids. While this therapy can be effective for a time, after one to two years abiraterone-treated patients typically relapse.
Balk and colleagues (Cai et al., 2011) have previously shown that abiraterone therapy can select for increased expression of CYP17A1, thereby increasing the production of downstream steroid products and counteracting the inhibition mediated by abiraterone. In the current study by Chen et al., the authors demonstrate that in biopsies from three patients suffering from castration-resistant prostate cancer and treated with abiraterone, deep sequencing of tumor tissue reveals the existence of cells bearing a mutation (T878A) in AR that increases the binding and functional activation of signaling by another steroid associated primarily with female physiology, specifically progesterone. Analysis of a radical prostatectomy specimen from another patient also revealed the presence of the AR T878A mutation in part of this patient’s tumor.
The authors also found that the T878A mutation of AR also increased the potency of an AR antagonist, dutasteride, used to treat castration-resistant prostate cancer.
These results are of interest from both clinical and basic science perspectives. In the clinical context, obviously it is important to be aware of the possibility of abiraterone resistance and the potential value of therapy with a direct AR antagonist such as dutasteride.
For those interested in the relevance of evolution to medicine, treatment-related selection for a switch in AR ligand specificity in the context of treatment for castration-resistant prostate cancer provides yet another clinically-important example of the potential for somatic cell evolution to subvert therapy. The particular mutation of interest, AR T858A, which causes AR to bind progesterone well enough to generate signaling able to sustain prostate cancer cell survival and proliferation, also effectively illustrates the relentless of opportunism of evolution by natural selection.
Another theme explored in this space and elsewhere (Greenspan, 2011) relates to the nature of biological function on the molecular level. Clearly, the functions associated with progesterone cannot sensibly be attributed to progesterone in isolation. The effects of the hormone ultimately depend on the physical interactions it can engage in with other molecules, most notably receptors that then can generate cascades of additional molecular interactions or transformations, what we commonly refer to as signal transduction. Thus, in many instances, molecular functions are properties of intermolecular relationships more than properties intrinsic to individual molecules themselves.
Cancer Prevention and Control. http://www.cdc.gov/cancer/dcpc/data/men.htm. Last accessed on 2/28/15.
Chen E, Sowalsky AG, Gao S, Cai C, Voznesensky O, Schaefer R, Loda M, True LD, Ye H, Troncoso P, Lis RT, Kantoff P, Montgomery B, Nelson PS, Bubley GJ, Balk SP, Taplin ME. Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors. Clin Cancer Res. 2014 Oct 15. pii: clincanres.1220.2014. [Epub ahead of print] PubMed PMID: 25320358.
Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, Marck B, Matsumoto AM, Simon NI, Wang H, Chen S, Balk SP. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011 Oct 15;71(20):6503-13. doi: 10.1158/0008-5472.CAN-11-0532. Epub 2011 Aug 25. PubMed PMID: 21868758; PubMed Central PMCID: PMC3209585.
Greenspan NS. Attributing functions to genes and gene products. Trends Biochem Sci. 2011 Jun;36(6):293-7. doi: 10.1016/j.tibs.2010.12.005. Epub 2011 Jan 25. PubMed PMID: 21269834.