Targeting CDC7 Overcomes Gemcitabine Resistance in Cholangiocarcinoma by Inducing Cellular Senescence

Advanced-stage cholangiocarcinoma (CCA) frequently develops resistance to chemotherapy, highlighting an urgent unmet need for novel therapeutic strategies. Here, we analyzed 16 pairs of CCA and adjacent non-tumor tissues, and demonstrated that dysregulation of the cell cycle machinery is a hallmark of CCA, closely associated with chemoresistance and poor prognosis. Targeting aberrant cell cycle regulation therefore represents a promising approach to improve current treatment outcomes. We identify the CDC7 inhibitor XL413 as an effective agent capable of re-sensitizing gemcitabine-resistant tumors across multiple preclinical models of CCA. Mechanistic analyses, including transcriptomic profiling, reveal that combination therapy activates senescence-associated pathways, with therapeutic efficacy is mediated via a ROS-DNA damage-senescence cascade. Notably, synergistic induction of cellular senescence is observed in CCA cells upon co-treatment with a CDC7 inhibitor and gemcitabine. Collectively, these findings provide robust preclinical evidence supporting the combination of gemcitabine and CDC7 inhibitors as a viable therapeutic strategy to enhance the clinical management of CCA.