The DNA Minor Groove Binders Trabectedin and Lurbinectedin are Potent Antitumor Agents in Human Intrahepatic Cholangiocarcinoma

Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) is the second most common type of primary liver tumor. Due to its aggressive nature and resistance to conventional treatments, there is a pressing need to develop novel and more effective therapies for this deadly malignancy. Methods: Here, we explored the therapeutic potential of the DNA minor groove binders Trabectedin (TRB) and Lurbinectedin (LUR) for the treatment of iCCA using cell lines, spheroids, cancer-associated fibroblasts (CAFs), patient-derived tumor organoids (PDOs), and the chicken corioallantoic membrane (CAM) in vivo model. Results: TRB and, more substantially, LUR, significantly inhibited cell growth in iCCA cell lines, spheroids, CAFs, and patient PDOs at very low nanomolar concentrations. Specifically, the two drugs significantly reduced proliferation, triggered apoptosis, and caused DNA damage in iCCA cells. At the metabolic level, TRB and LUR decreased mitochondrial respiration and glycolysis. At the molecular level, the two compounds effectively downregulated the mTORC1 and Hippo/YAP pathways and suppressed the expression of YAP1, c-Myc, E2F1, BRD4, TEAD4, and CD7 proto-oncogenes. Furthermore, LUR significantly restrained the in vivo growth of iCCA cells in the CAM model. Conclusions: Our data indicate that TRB and LUR possess strong antiproliferative and pro-apoptotic activities and could represent promising therapeutic agents for the treatment of iCCA.