Abstract 285: Androgen receptor splice variants determine taxane sensitivity in prostate cancer

Androgen ablation therapy is the mainstay for prostate cancer (PC) treatment, however, it is not curative, as many patients progress to a castration-resistant stage (CRPC). CRPC remains driven by active androgen receptor (AR) signaling. Several AR splice variants lacking the ligand binding domain were recently identified in PC. These variants are constitutively active in the nucleus, rise in response to castration, and are thought to mediate disease progression in CRPC. Taxane chemotherapy improves survival in CRPC. We have recently shown that taxanes impair the ligand-induced nuclear accumulation and transcriptional activity of full-length AR (AR-FL), downstream of microtubule (MT) stabilization. This is due to AR binding MTs and using them for its nuclear accumulation with the aid of the dynein motor protein. However, the effect of taxane treatment on the nuclear accumulation and activity of the AR variants is not known. As the variants are expressed in CRPC, we sought to examine the mechanism underlying AR variant nuclear accumulation and the impact of taxane treatment on their function. We have focused our studies on two clinically relevant AR splice variants ARv567 and AR-V7 and assessed their ability to bind MTs, translocate to the nucleus with dynein and response to taxane treatment. Our data showed that the two variants behave differently on all aspects. Microtubule co-sedimentation revealed that ARv567 is associated with MTs, in contrast to the significantly reduced association displayed by AR-V7. Dynamitin overexpression inhibited the nuclear accumulation of AR-FL and ARv567 but had no effect on AR-V7, suggesting that AR-V79s nuclear translocation is independent of dynein-based MT transport. To examine the impact of taxane treatment on variant activity we microinjected GFP-tagged AR-FL, or variants into the nucleus of PC3 cells and monitored the dynamics of AR nuclear translocation using live-cell confocal microscopy and AR transcriptional activity using ARE luciferase reporter assay. Our data showed that taxanes significantly inhibited the nuclear accumulation and activity of AR-FL and ARv567 but not that of AR-V7. Human xenograft models expressing the ARv567 exhibited greater tumor volume decreases in response to taxane treatment as compared with xenografts expressing either AR-FL or other variants. Taken together our data reveal that functional MTs are required for AR9s nuclear transport in a ligand independent manner, as in the case of ARv567. However, this does not apply to AR-V7 which is not under MT control and thus, remains insensitive to taxane treatment. We are currently narrowing down the MT binding domain on the AR by serial mutagenesis and are testing their MT binding abilities. These data suggest that inhibition of AR nuclear accumulation underlies, in part, the activity of taxanes in CRPC and that the presence of the variants may determine the clinical efficacy of taxane chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 285. doi:1538-7445.AM2012-285