AR F877L

We also assessed the efficacy of target protein degraders (TPDs), such as ARV-110 and ARV-667, in both models, and the corresponding validation data are also included here.

HP518, a novel AR PROTAC degrader, demonstrates in this Phase 1a dose-escalation study, an acceptable safety/tolerability profile and a signal of efficacy in an unselected mCRPC patient population. The presence of AR LBD mutations may predict benefit from HP518, and merits further investigation in pts with mCRPC. Clinical trial information: NCT05252364.

Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC.

AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide. >1n (%).

Commonly found mutations include L702H, W742C, H875Y, F877L and T878A, while the F877L mutation can convert second-generation antagonists such as enzalutamide and apalutamide into agonists. However, pruxelutamide, another second-generation AR antagonist, has no agonist activity with the F877L and F877L/T878A mutants and instead maintains its inhibitory activity against them...Additional structural studies suggest that both the L702H and F877L mutations are important for conformational changes. This structural variability in the AR LBD could affect ligand binding as well as the resistance to antagonists.

Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation...Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively... AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. >

In this large database, the overall detection rate of activating AR-LBD mutations in men with mCRPC undergoing ctDNA analysis was 21%, and increased with prior use of 2nd generation ARPi (abiraterone and enzalutamide). Men with AR-LBD mutations were more likely to harbor other alterations relevant to tumor progression. These findings inform on the ctDNA prevalence and impact of AR-LBD mutations in a real-world dataset of mCRPC.

The proteins' motion and FEL further validated the aforementioned findings where the wild type reported different dynamic features than the mutant complexes. In conclusion, this study provides a structural basis for the resistance to Enzalutamide, which can be used to design novel effective drugs using structure-based and rationale approaches.

This assay is applicable to determine a wide range of clinical AR mutants including those with loss of function relating to androgen insensitivity syndrome (AIS), and those associated with PCa conferring resistance to AR antagonists such as enzalutamide (ENZ), bicalutamide (BIC), and cyproterone acetate (CPA). One clinical AR mutant previously reported to confer ENZ-resistance, F877L, was found to confer partial resistance to CPA as well using designer yeast. Our simple and efficient assay can enable precise one-pot screening of AR mutants, providing a reference for tailored medicine.

Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Therefore, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy.

AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure-activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC.

The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).

Furthermore, combining chemical V-ATPase inhibition with the AR antagonist enzalutamide resulted in a greater reduction in AR downstream target expression than enzalutamide alone in LNCaP cells...Overall, these results indicate that V-ATPase dysregulation is directly linked to both hormone responsive and CRPC via impact on AR function. In particular, V-ATPase inhibition can reduce AR signaling regardless of mutant AR expression.

The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non-AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.