Аннотация
Abstract We recently reported that nuclear localized membrane proteins (NLMP) play essential roles in drug adaptive mediated cancer evolution. Nuclear receptor tyrosine kinases (nRTKs), one of NLMP family, are aberrantly elevated in many human cancers. For example, nMET promotes cancer evolution through stem cell mediated drug resistance and homeostasis of cell survival. However, MET inhibitor mediated adaptive resistance frequently occurs by which nMET induction and other signaling mechanisms are involved. We previously showed androgen deprivation therapy (ADT) can induce nMET accumulation in castration resistant prostate cancer (CRPC) patient specimens, while membrane MET is primarily elevated in naïve prostate cancer (PCa) tumors. In addition to androgen deprivation enhanced NLMP, DNA damage targeting chemotherapy can also induce adaptive escape for survival while nonstem cell-like nMET expressing cells may undergo clearance by cell death through cell cycle arrest induced by p21 and DNA damage response as we reported previously. Here we further applied carbon nanodots to examine the combination effect on CRPC cells survival to target NLMP. We found beet derived carbon nanodots can enter into nucleus and induce DNA damage in PC3 cells. The DNA damage is prevented in nucleolus region and opposed by BRCA1 in nucleus. Most importantly, carbon nanodots suppressed tumor growth of PC3 cells in xenograft models in vivo in a PARP-dependent manner. Finally, we found beet derived carbon nanodots exhibit stem cell marker, phosphatase-like nanozyme activity and promote phosphatase activity. Thus, potential stemness induced by carbon nanodots may interfere the efficiency of anti-cancer by DNA damage. Then we applied phosphatase inhibitor for further enhanced inhibition of cell growth by targeting PARP with AZD-2281 in combination of carbon nanodots and phosphatase inhibitor. Our findings reveal for the first time that targeting CRPC by carbon nanodots can be a novel avenue for inhibiting RTK/nRTK/nMET in nucleus of prostate cancer cells. Taken together, our data suggest green carbon nanozyme mediated combination therapy with RTK/MET/NLMP inhibitors would be an innovation in targeted therapy to prevent drug resistance. Citation Format: Yingqiu Xie, Haiyan Fan, Limara Manarbek, Ayan A. Nurkesh, Qing Yang, Aisulu Maipas, Zhenbang Chen. Targeting NLMP prevents drug adaptive prostate cancer evolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 134.