Study On The Androgen Receptor Antagonsists Resistance Mechanisms Induced By Amino Acid Mutations

Next to lung cancer,prostate cancer(PCa)is one of the main causes of male deaths from cancer.It has obvious geographical and ethinic differences,especially in European and American developed countires and regions.Although the incidence rate of prostate cancer in China is far low than Europe and America,with the accelerating aging process and the improvement of diagnosis,the incidence rate of prostate cancer has risen over recent years.Prostate cancer cell initially depends on androgen for growth,which can regulate the proliferation of prostate tumor cells,so androgen receptor(AR)as a main target plays a pivotal role for the treatment of prostate cancer.The standard treatment approach involves surgical androgen ablation in conjunction with antiandrogens to block the remaining levels of AR activity.There are two kinds of AR antagonists,steroidal and non-steroidal chemicals.Due to the side effects of steroidal AR antagonists,it leads to the rapid development of non-steroidal AR antagonsts.Non-steroidal ligands,including flutamide,whose active form is hydroxyflutamide(HF),nilutamide,R-bicalutamide(R-bic)and enzalutamide(Enza)etc.,are more advantageous for clinical applications because there is little cross-reactivity with other steroid receptors.Although this kind of treatment is effective at the beginning,the antiandrogens will soon lose efficacy,with the emergence of the recurrent and metastatic forms of castration-resistant PCa(CRPC).One of the key reasons for resistance is the mutation of the AR in the ligand binding domain(LBD),which can switch the AR antagonists to agonists or partial agonists.In the first part of this thesis,we firstly introduced prostate cancer,mainly including the current trend,the diagnosis,staging and treatment of prostate cancer and the castration of recurrent prostate cancer.Then,the structure of the androgen receptor and the application in prostate cancer were introduced.Finally,androgen receptor-related drug resistance mechanism was described.In the second and third chapters,we employed molecular dynamics(MD)simulations to study the effects of androgen receptor mutations on hydroxyflutamide and R-bicalutamide.Our simulations in explicit solvent show that different mutations cause drug resistance by changing the conformation of H12 or have different interaction mode with key residues of LBD.In the forth part,we also used MD simulations to study the effects of AR mutations on enzalutamide.The results show that H12 lies on the top of the AR LBD plays a vital role for the function of enzalutamide.When the C-ring of enzalutamide locates near to H12,the distance between enzalutamide and H12 is reduced,which prevents H12 from closing and distort the coactivator binding site,resulting in the inactivation of transcription.In this case,enzalutamide acts as an AR antagonist.However,when the C-ring is away from H12,H12 tends to close to form a coactivator binding site to facilitate transcription,enzalutamide acts as an AR agonist.In this paper,molecular dynamics simulations and binding free energy calculations were applied to study the interaction mechanism between wild type(WT)/mutant ARs and hydroxyflutamide,R-bicalutamide and enzalutamide.The results are helpful to the rationally screen and design of new AR antagonists.