Targeting ARPC1B+ Cancer Stem Cells to Sensitize Pancreatic Cancer to Gemcitabine Treatment

Pancreatic cancer is a highly aggressive malignancy and poses significant therapeutic challenges due to resistance to conventional therapies. Cancer stem cells (CSCs) act as key contributors to this resistance with their self-renewal capacity. In this study, we identified the ARPC1B+ CSC subpopulation specifically resistant to gemcitabine through integrated analysis of scRNA-seq and bulk RNA-seq data from pancreatic cancer samples. Additionally, ARPC1B expression was significantly elevated in gemcitabine-resistant CSCs and correlated with higher mutation burden and intra-tumor heterogeneity. Molecular docking analysis identified CK-636 as a potential ARPC1B-targeting agent with high affinity. Ex vivo and in vivo experiments demonstrated that combinational therapy of gemcitabine along with CK-636 could significantly inhibit tumor growth compared to gemcitabine alone, indicating that targeting ARPC1B+ CSCs can sensitize pancreatic cancer to gemcitabine treatment. These findings highlight ARPC1B+ CSCs as a promising therapeutic target for overcoming gemcitabine resistance in pancreatic cancer.