Prostate cancer is driven by the androgen receptor (AR) even in advanced stages. Despite the advent of potent second-generation therapeutic agents targeting AR such as enzalutamide, darolutamide and apalutamide, oncogene addiction to AR is manifested in significant increases in the expression of the full-length receptor (AR-FL) and alternatively spliced AR variants (AR-Vs) such as the AR-variant 7 (AR-V7). AR-Vs lack the AR-FL ligand-binding domain and are resistant to AR-targeting agents (that target the ligand-binding domain). Indeed, detection of expression of AR-Vs in circulating tumor cells correlates with resistance to therapies to drugs targeting the AR ligand-binding domain. Since AR-Vs have intact AR DNA-binding and transactivation domains, they have the capability to independently bind to DNA, activate transcription and mediate DNA damage repair. However, since AR-Vs are almost always co-expressed with AR-FL and can form heterodimers with AR-FL, the AR-FL-independent activity of AR-Vs in a prostate cancer cell that expresses both AR-Vs and AR-FL was not known. This question has important clinical implications:  if AR-Vs functioned effectively independent of AR-FL, then more potent drugs targeting AR-FL alone would not block AR signaling in advanced prostate cancer.

To decipher the AR-FL-independent activity of AR-Vs, AR-Vs incapable of heterodimerization with AR-FL are needed. We discovered that a mutation in the FXXLF motif of AR-V7 (AR-V7^Fmt) blocked its ability to heterodimerize with AR-FL. AR-V7^Fmt formed homodimers and was found to be largely nuclear. Importantly, AR-V7^Fmt did not enable nuclear localization of unliganded AR-FL. Using Chromatin immunoprecipitation studies, we showed that AR-V7^Fmt bound to DNA corresponding to AR-responsive elements on gene promoters. RNA-sequencing studies indicate that AR-V7^Fmt drives a canonical AR transcription program and regulates DNA damage repair in response to radiation. These data taken together indicate for the first time that, when co-expressed with AR-FL in prostate cancer cells, AR-Vs can function independently of their ability to interact with AR-FL and perform canonical AR functions. These data also suggest that therapeutic approaches to target AR-Vs may offer benefit to patients with advanced prostate cancer. Finally, these data critically establish that AR-Vs are more than just a biomarker of advanced prostate cancer and may contribute to oncogene addiction of advanced prostate cancer to AR.

Link to the paper: https://rdcu.be/ccgmg