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.胰腺癌是一种高侵袭性恶性肿瘤，由于对常规治疗产生耐药性，其临床治疗面临重大挑战。癌症干细胞（Cancer Stem Cells, CSCs）凭借自我更新能力，是导致此类耐药性的关键因素。本研究通过对胰腺癌样本的单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）与bulk RNA测序（bulk RNA sequencing, bulk RNA-seq）数据进行整合分析，鉴定出了对吉西他滨具有特异性耐药性的ARPC1B阳性癌症干细胞亚群。此外，在吉西他滨耐药的癌症干细胞中，ARPC1B的表达水平显著升高，且与更高的突变负荷及肿瘤内异质性密切相关。分子对接分析结果显示，CK-636是一种对ARPC1B具有高亲和力的潜在靶向药物。体外与体内实验均证实，相较于单独使用吉西他滨，吉西他滨联合CK-636的治疗方案可显著抑制肿瘤生长，这表明靶向ARPC1B阳性癌症干细胞能够使胰腺癌对吉西他滨治疗重新敏感。本研究结果凸显ARPC1B阳性癌症干细胞作为克服胰腺癌吉西他滨耐药性的极具前景的治疗靶点。