The androgen receptor (AR) is a critical driver of prostate cancer progression and the advent of androgen receptor pathway inhibitors (ARPIs) has transformed the treatment landscape of metastatic prostate cancer. However, resistance to ARPIs eventually develops via mutations in AR, AR overexpression, and alternative AR signaling which have required novel approaches to target effectively.
The mechanism of action and early clinical results of proteolysis targeting chimera (PROTAC) agents targeting AR are reviewed. Preclinical and early clinical data for other emerging AR-targeting therapeutics, including dual anti-androgen receptor inhibitors (DAARIs) and anitens that target the N-terminal domain (NTD) of AR, were also identified through literature search for agents which may circumvent resistance through AR splice variants and AR LBD mutations. The literature search utilized PubMed to identify articles that were relevant to this review from 2000 - 2024.
PROTACs, DAARIs, and anitens represent novel and promising AR-targeting therapeutics that may become an important part of prostate cancer treatment in the future. Elucidating mechanisms of resistance, including ability of these agents to target full length AR, may yield further insights into maximal therapeutic efficacy aimed at silencing AR signaling.
Expert review of anticancer therapy. 2024 Jul 18 [Epub ahead of print]
Peter D Zang, Allen Seylani, Evan Y Yu, Tanya B Dorff
City of Hope Comprehensive Cancer Center, Duarte, CA, USA., University of California Riverside School of Medicine, CA, USA., Fred Hutchinson Cancer Center, Seattle, WA, USA.