Functional Investigation and Development of Potential Inhibitors of Kinetochore Associated Proteins in Cisplatin Resistance Cancer Cells

Worldwide, around 12.7 million cancers are diagnosed and 7.6 million people die of cancer each year. Cisplatin is the most commonly used chemotherapeutic drug for the treatment of tumors, such as ovarian, head and neck, esophageal, lung, bladder, cervical, and testicular cancers. Patients are highly responsive to initial treatment, but at advanced stage usually suffer from recurrence or metastasis due to cisplatin resistance. Therefore, a better understanding of the molecular mechanisms of cisplatin resistance could improve the efficacy of chemotherapy. Through analyzed cisplatin resistance signatures, we found kinetochore associated proteins up-regulated in various cisplatin-resistant cells and no research evidence to support a causal relationship between kinetochore associated proteins and cisplatin resistance. The main objectives of this proposal are to investigate and clarify the functional role of kinetochore associated proteins in the cisplatin-resistant cells, and investigate the potential application of modulating this molecular in cancer treatment. The experimental designs of this study are as follows： (1) Characteristic cellular functions and effect of cisplatin sensitivity of kinetochore associated proteins (2) identification of networks pathways and regulatory proteins through integrating bioinformatic analysis (3) identification of kinetochore associated proteins inhibitors to reverse cisplatin resistance through drug database comparison, and (4) validation of kinetochore associated proteins or inhibitors using animal models. We expect the results from this study may provide complete information of cisplatin resistance and improve the treatment efficacy.