BERKELEY, CA (UroToday.com) - We recently published a review in the journal Anticancer Research that focused on resistance of castration resistant prostate cancer (CRPC) to abiraterone. The literature review was performed using the PubMed (United States National Library of Medicine National Institutes of Health) database for articles published up to June 1, 2014.
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Androgen receptor (AR) and AR signaling have key roles in prostate cancer development, progression, response to initial hormonal therapy, and subsequent resistance to it. Several genetic and epigenetic mechanisms have been described whereby prostate cancer may progress to the lethal castration-resistant form. Generally, they include a number of mechanisms such as: AR amplification/overexpression, alternative sources of androgens, mutated or promiscuous AR, and overexpression of AR co-regulators, which keep the androgen-responsive program active despite castration.[1, 2] Both clinical and pre-clinical data suggest that resistance to novel drugs, like abiraterone, is also associated with the reactivation of AR signaling, due to different causes. What this suggests is that among the mechanisms that more generally lead to CRPC, may be found causes of treatment resistance.
In this review, we dealt with the mechanisms that, in our opinion, could contribute to development of abiraterone resistance in CRPC. On these bases we reviewed the current literature and we selected the following topics: the importance of the AR splice variants (i.e., AR-V7), the up-regulation of CYP17A1, the AR activation by non-canonical ligands (i.e., the exogenous corticosteroids used to reduce side effects of abiraterone or the steroid precursors upstream of CYP17A), the preventing DHT loss and glucuronidation pathways,[4, 5] the microRNAs (many studies suggest that miRNAs are modulators of AR signaling, regulating AR gene expression and its targets; conversely, evidence suggests that miRNAs may be regulated by androgens),[6, 7]and the possible role of other pathways (i.e., pre-clinical studies show that the AR and PI3K-AKT signaling pathways cross-regulate each other by reciprocal feedback).
As these are only hypotheses, we know that their real function should be investigated in patients under treatment with abiraterone. Thus, future studies on the tailored therapy of prostate cancer might be helped via the identification of predictive biomarkers of response to CYP17A1 inhibitors.
- Aschelter AM, Giacinti S, Caporello P and Marchetti P: Genomic and epigenomic alterations in prostate cancer. Front Endocrinol 3: 128, 2012
- Ferraldeschi R, Welti J, Luo J, Attard G and De Bono JS: Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene 19: 1-13, 2014
- Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Chen Y, Roeser JC, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR,Carducci MA, Eisenberger MA and Luo J: Androgen receptor splice variant, AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 32: 5s, 2014
- Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB and Wilson EM: Activation of the androgen receptor by intratumoral bioconversion of androstenediol to dihydrotestosterone in prostate cancer. Cancer Res 71: 1486-1496, 2011
- Belanger A, Pelletier G, Labrie F, Barbier O and Chouinard S: Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans. Trends Endocrinol Metab 14: 473-479, 2003
- Waltering KK, Porkka KP, Jalava SE, Urbanucci A, Kohonen PJ, Latonen LM, Kallioniemi OP, Jenster G and Visakorpi T: Androgen regulation of microRNAs in prostate cancer. Prostate 71: 604-614, 2011
- Ostling P, Leivonen S-K, Aakula A, Kohonen P, Makela R, Hagman Z, Edsjo A, Kangaspeska S, Edgren H, Nicorici D, Bjartell A, Ceder Y, Perala M and Kallioniemi O: Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. Cancer Res 71: 1956-1967, 2011
- Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT, Rosen N and Sawyers CL: Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN deficient prostate cancer. Cancer Cell 19(5): 575-586, 2011
Silvana Giacinti as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Oncology, Faculty of Medicine and Psychology, Sapienza University of Rome, Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy