Riley Latham

Background: Castration-resistant prostate cancer (CRPC) is “the main cause of cancer related death among men in the world”¹. It poses a formidable challenge in oncology due to its resistance to standard treatments like Androgen Deprivation Therapy (ADT). Alternative gene splicing, particularly the expression of the androgen receptor variant AR-V7, contributes to CRPC progression and treatment resistance². Understanding the role of AR-V7 as a biomarker and its impact on treatment outcomes is crucial for improving patient management in CRPC.

Objective: In this review the implications of AR-V7 are investigated as well as differing new ways in which CRPC patients can be treated by degrading AR-V7.

Search Methods: An online search in PubMed database from 2018-2023 was performed using “CRPC”, “AR-V7”, “AR-V& degradation”, and “AR-V7 drug resistance” .

Results:  RT-PCR was performed on captured epithelial cells from CRPC patients’ blood before having begun their second line treatment revealed that AR-V7, AR-FL, and CTC are all linked with more progressed disease states, but AR-V7 in particular is indicative of worse overall survival³, this finding is clinically useful because it suggests that AR-V7 is an important biomarker. Studies evaluating the effectiveness of Taxanes and ARSIs in CRPC treatment have highlighted the importance of AR-V7 status in predicting treatment response. Patients positive for AR-V7 exhibit better survival rates with Taxanes, whereas those negative for AR-V7 respond more favorably to ARSIs.⁴ Mechanistic studies have identified KIF15 as a key regulator of AR-V7 stability, providing a potential target for novel therapeutic interventions. KIF15 stabilizes AR-V7 by allowing the deubiquitinating enzyme USP14 to associate with AR-V7 so that AR-V7 is not degraded and stays transcriptionally active.⁵ Moreover, natural compounds like nobiletin and rutaecarpine have shown promise in promoting AR-V7 degradation and sensitizing CRPC cells to chemotherapy drugs^{6, 7}. Nobiletin causes the cell cycle to arrest at G0/G1 and promotes a form of K48-ubiquitinated AR-V7. Nobiletin prevented the deubiquitinating enzyme USP14 from associating with AR-V7, allowing for further degradation⁶. Rutaecarpine promotes a form of AR-V7 that is complexed with the ER chaperone GRP48. GRP48 allows it to complex with the ligase SIAH2 as well. In this form, AR-V7 can be degraded⁷.

Conclusions: AR-V7 serves as a valuable biomarker for guiding treatment decisions in CRPC, with implications for personalized medicine approaches. Targeting AR-V7 and its associated pathways, including KIF15-mediated stabilization, presents new avenues for therapeutic development. Additionally, natural compounds offer alternative strategies to combat CRPC progression and drug resistance. Future research should focus on validating the efficacy of KIF15 inhibitors and exploring the clinical utility of natural compounds in larger cohorts of CRPC patients, as well as why it is that AR-V7 patients have better outcomes with Taxanes instead of ARSIs, with the ultimate goal of improving treatment outcomes and patient quality of life.

Works Cited:

1. Cai M, Song XL, Li XA, et al. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resist Updat. 2023;68:100962. doi:10.1016/j.drup.2023.100962
2. Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. Nat Rev Dis Primers. 2021;7(1):9. Published 2021 Feb 4. doi:10.1038/s41572-020-00243-0
3. Cattrini C, Rubagotti A, Zinoli L, et al. Role of Circulating Tumor Cells (CTC), Androgen Receptor Full Length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a Prospective Cohort of Castration-Resistant Metastatic Prostate Cancer Patients. Cancers (Basel). 2019;11(9):1365. Published 2019 Sep 13. doi:10.3390/cancers11091365
4. Graf RP, Hullings M, Barnett ES, Carbone E, Dittamore R, Scher HI. Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer. Eur Urol. 2020;77(2):170-177. doi:10.1016/j.eururo.2019.08.020
5. Gao L, Zhang W, Zhang J, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039. doi:10.1158/0008-5472.CAN-20-1965
6. Liu Y, Yu C, Shao Z, et al. Selective degradation of AR-V7 to overcome castration resistance of prostate cancer. Cell Death Dis. 2021;12(10):857. Published 2021 Sep 21. doi:10.1038/s41419-021-04162-0
7. Liao Y, Liu Y, Xia X, et al. Targeting GRP78-dependent AR-V7 protein degradation overcomes castration-resistance in prostate cancer therapy. Theranostics. 2020;10(8):3366-3381. Published 2020 Feb 10. doi:10.7150/thno.41849