Construction Of Enzalutamide Resistance Model In Vitro And Enzalutamide Resistance Mediated AR Hypersensitivity

The current treatment methods for prostate cancer include androgen deprivation therapy(ADT),surgical treatment,radiotherapy and chemotherapy.The core of drug treatment is around the androgen receptor pathway.At present,the treatment of androgen receptor signal inhibitors such as Enzalutamide has gradually become the mainstream treatment method,but with the progress of treatment,patients will eventually develop into drug-resistant prostate cancer.Androgen receptor(AR)still plays an important role in the stage of metastatic hormone-sensitive prostate cancer.There are many treatment methods for patients with metastatic hormone-sensitive prostate cancer,and ADT combined with azalumide is recommended in several guidelines.However,when these patients are resistant to enzalutamide,the patients have less treatment options and poor prognosis.Patients with hormone sensitive prostate cancer have been using enzalutamide for longer periods of time,and the resistance mechanism may not be the same as that of the CRPC stage.And research shows that some patients have progressed to neuroendocrine prostate cancer(NEPC)after receiving enzalumide treatment,and AR transcription Reprogramming is involved in the process of NEPC.In order to further determine what changes have taken place in the process of drug resistance to enzalutamide and neuroendocrine changes,we constructed Nzaluamine-resistant cell(LNCaP-ENZR and C4-2-ENZR).Our results indicate that the DHT concentration required for the growth of enzalutamide resistant prostate cancer cells is lower than that required for non resistant prostate cells,suggesting that AR may become more sensitive.In LNCaP-ENZ cells,AR is mainly present in the nucleus.AR is distributed both inside and outside the nucleus in the C4-2 cell line,and the number of AR in the nucleus of C4-2-ENZR cells more than C4-2 cells.AR has significantly increased stability in Enzalutamide-resistant prostate cancer cells.Hormone sensitive prostate cancer and castration resistance prostate cancer(CRPC)exhibit similar changes in AR after resistance to enzalutamide.In addition,based on our sequencing results,compared to C4-2-ENZR cells,LNCaP-ENZ cells are more likely to transition to NEPC,and some of their AR pathways are in an inhibitory state.May be differential expression of VEGFA and WDR3 involved in this process.