Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Version 1 : Received: 28 September 2021 / Approved: 1 October 2021 / Online: 1 October 2021 (12:19:03 CEST)

How to cite: Jacob, A.; Raj, R.; Allison, D.B.; Myint, Z.W. Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies. Preprints 2021, 2021100016 (doi: 10.20944/preprints202110.0016.v1). Jacob, A.; Raj, R.; Allison, D.B.; Myint, Z.W. Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies. Preprints 2021, 2021100016 (doi: 10.20944/preprints202110.0016.v1).

Abstract

Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor- abiraterone and androgen receptor antagonists- enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

Keywords

prostate cancer; castrate-resistant growth; metastases; androgen receptor; glucocorticoid receptor; cytokines; transmembrane receptors; cell signaling; pharmacological targeting; neuroendocrine differentiation; lineage plasticity; prostate cancer stem cells

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