Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

Prostate cancer cells rely critically on the androgen receptor AR for initiation, growth and progression to castration resistant prostate cancer CRPC -providing a compelling molecular basis for it as a therapeutic target. Enzalutamide or MDV3100, an AR antagonist, is now routinely used for the treatment of CRPC patients. Enzalutamide impedes both the nuclear translocation and chromatin recruitment of AR. However, recent studies reveal that while Enzalutamide provides palliative benefits, even the most responding patients relapsed within 2 years. AR, being a versatile transcriptional co-activator, interacts with critical proteins to adapt rapidly to androgen deprivation. In recent years, distinct AR modifications, have garnered considerable attention, primarily due to their direct correlation with pathogenic AR activation in CRPCs. Notably, some of these mechanisms confer both androgen-independence and anti-androgen resistance to PC cells -an underlying basis for their clinical association with hormone refractory and metastatic prostate cancers. The hypothesis is that CRPCs could endow super-penetrance to AR, via camouflaging it with post-translational marks. Modified AR can translocate to the nucleus in the presence of Enzalutamide due to its tight association with the modifying enzymes. Subsequently, super-penetrant phosphoAR, is recruited to the chromatin in an androgen independent manner to regulate distinct transcription program, making CRPC cells resistant to Enzalutamide treatment. Importantly, this proposal will use an innovative chemical proteomics- mass spectrometry based method to uncover novel targets and inhibitors to overcome Enzalutamide resistance of CRPCs. The objectives are First, examine whether modifications in AR promote differential association with Enzalutamide. Second, determine whether Enzalutamide-bound phosphoAR translocates to the nucleus and is recruited to the AR- target gene promoters.