Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants

David Olmos

Over 900,000 new cases of prostate cancer are diagnosed worldwide each year. Prostate cancer is the second commonest cause of male cancer-related death in the United States and the sixth worldwide with more than 250,000 deaths each year.

Despite major advances in the management of advance prostate cancer, mainly due to the introduction of androgen-deprivation therapy (ADT) many patients will eventually succumb to their disease due to the emergence of castration-resistance. The central role of androgens and the androgen receptor (AR) in castration-resistant prostate cancer (CRPC) is, paradoxically, echoed by the common, albeit erroneous, use of the terms ‘hormone resistant’ and ‘androgen independent’. Nonetheless, the progression of prostate cancer despite ongoing abrogation of androgen signalling is likely to be related to the limited effectiveness of classical androgen-deprivation therapy rather than the cancer cells gaining genuine autonomy from AR-signalling pathways.

This point is vividly illustrated in recent reports on specific inhibitors of CYP17 (that is key to androgen and oestrogen synthesis) such as abiraterone acetate; or novel AR antagonist such as MDV3100 which have sown significant and durable clinical activity in CRPC, thus confirming the continued dependency of CRPC on AR signalling pathway.

Promising results in initial Phase I and/or II studies led to a phase III study with abiraterone acetate which showed a survival advantage over prednisolone alone in patients with CRPC pretreated with docetaxel. After an expedited 6-months review the FDA approved this treatment in April 2011. Still, many men will not respond to abiraterone or will ultimately progress. The mechanistic basis of resistance to abiraterone has not been completely elucidated.

In this preclinical study reported by Mostaghel et al in Clinical Cancer Research the authors aimed to address the effect of abiraterone on prostate cancer androgen activity and to identify potential resistance mechanisms using CRPC xenografts in castrate male mice.
Abiraterone is well known to inhibit CYP17 activity in vitro. However, it remained unclear whether this ability was due to suppression of intratumoral androgens (as opposed as other systemic sources of androgens). In this study, Mostaghel et al has elegantly show that abiraterone administration resulted in marked suppression of intratumoral androgens.  This suppression was achieved at early time-points and usually maintained at later time-points, although a trend toward reconstitution of initial level was observed in some resistant tumours xenograft (tumours recurred within 21-days) before abiraterone was interrupted. The inhibition of testosterone synthesis by abiraterone resulted in PSA responses and tumour shrinkage, but not in the controls.

Mostaghel et al studied the changes in AR, AR-regulated genes and androgens synthesis related genes. The authors report an increase in expression of CYP17A and other key enzymes mediating androgen synthesis observed in the CRPC as well as in the expression of full-length and truncated AR variants in abiraterone treated xenografts. Thus, we can say that the studied CRPC models responded to CYP17 inhibition with mechanisms to maintain AR signalling.

Although, clinical studies to date suggest that there is no increase in serum androgens at progression on abiraterone, this preclinical data support the hypothesis that resistance may be mediated by an increase in intratumoral androgen synthesis despite abiraterone. A second resistance mechanism suggested by the results of this study is the increased expression of full-length and split variants of the AR. Such expression could result in an enhanced AR response to very low ligand concentrations or alternatively ligand-independent AR activation. In any case, this results supports the simultaneous emergence of multiple resistance pathways in order to preserve the AR signalling. 

To conclude, this study provides key information to better understand how CYP17 inhibition works in CRPC; but it could also be very helpful to identify biomarkers of abiraterone resistance and to design novel strategies to inhibit the AR axis.

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