Screening and identification of kinases involved in drug resistance in bladder cancer

Abstract

Bladder cancer is the seventh most common cancer. Recurrence after surgical removal of tumours is common and nearly half of the patients present with muscle invasive disease or harbour occult distant metastases. In such cases effective systemic therapies aimed at eliminating micro-metastases may improve outcome. Most patients who initially respond to chemotherapy (methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin or carboplatin) relapse within the first year and the median survival is about 12 months. Consequently, there is a need to find drug targets that enhance the effects of existing chemotherapy and/or reverse drug resistance. Drug resistance is believed to cause treatment failure in >90% of patients with metastatic cancer, and resistant micro-metastatic cells may also reduce the effectiveness of adjuvant chemotherapy. We used a kinome-based siRNA screen in T24 bladder cancer cells to try and identify novel druggable regulators of chemoresistance in bladder cancer cells. The screen has identified 23 common kinases that sensitise and 2 that antagonise the cytotoxic effects of both cisplatin and paclitaxel in T24 cells upon knockdown. We have further identified 63 kinases that significantly alter the response of cells to cisplatin and 60 kinases that significantly change the viability response to paclitaxel. 13 of the hits were validated across two additional cell line and further work was done to elucidate the role of RSK4 in cancer. RSK4 not only sensitises bladder cancer cells to cisplatin and paclitaxel but it also has a role in migration in invasion. RSK4 seems to have a regulatory role which governs cancer metabolism, drug resistance and motility. Further studies are needed to clarify this role and specific inhibitors of RSK4 need to be developed in order to explore its potential use as a therapeutic target in cancer.