Targeting MCM10 disrupts cancer stemness and counteracts sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most prevalent primary malignant tumor, with sorafenib as the main treatment for advanced cases. However, the development of resistance to sorafenib, often driven by cancer stemness, significantly limits its therapeutic efficacy. Minichromosome maintenance complex component 10 (MCM10), a critical regulator of DNA replication and tumor progression, has been implicated in cancer stemness and therapeutic resistance. This study utilized datasets from TCGA and ICGC alongside in vitro and vivo experiments on clinical HCC tissues and sorafenib-resistant cell lines to evaluate MCM10's role in HCC. The Connectivity Map (CMap) was employed to identify TW-37, a potential gene silencing agent targeting MCM10 transcription. The effects of TW-37 on MCM10 expression, cancer stemness, and sorafenib sensitivity were assessed. Elevated MCM10 expression was observed in sorafenib-resistant HCC cell lines and was associated with poor patient outcomes. MCM10 knockout diminished cancer stemness and restored sorafenib sensitivity in resistant cells. Furthermore, TW-37, identified via CMap, effectively downregulated MCM10, reduced cancer stemness, and enhanced sorafenib efficacy, offering a promising therapeutic approach. MCM10 plays a pivotal role in promoting cancer stemness and sorafenib resistance in HCC. Targeting MCM10 transcription with TW-37 represents a novel strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients.