Novel chemotherapeutic agents against cisplatin-resistant cancers: a therapeutic strategy for cholangiocarcinoma

Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant biliary tumours with dismal prognosis. The first-line treatment for advanced CCA [cisplatin (CisPt) and gemcitabine] is considered palliative due to the high chemoresistance of this cancer, barely impacting on patients’ overall survival. CisPt is a platinum (Pt)-derived compound that binds to DNA, triggering single-strand DNA breaks and subsequent cancer cell death. This allows tumor cells to activate their DNA repair mechanisms against single-strand DNA breaks, hence, being able to survive and become resistant to CisPt. Taking into consideration the activity of platinum (Pt) derivatives and the resistance mechanisms developed by the tumour cells, we posited that novel Pt-derived chemotherapeutic agents displaying marked poly-electrophilic character could induce double-strand DNA breaks, thereby preventing the development of DNA repair mechanisms and promoting cancer cell death. This study aims to further evaluate the potential therapeutic impact of this novel family of Pt-derived chemotherapeutic agents, named Aurki-Pt, in CCA, one of the most aggressive cancers worldwide.