Inhibition of Pancreatic Cancer Stemness by the Novel CLK Inhibitor SM08502: Targeting Wnt Pathway and CSC Viability

The study focuses on the impact of SM08502, a newly developed inhibitor targeting the Wnt signaling pathway, on cancer stem cells (CSCs) in pancreatic cancer (PC). This pathway is crucial for the survival and propagation of CSCs, which are known to contribute to treatment resistance and tumor relapse. SM08502 has been shown to be effective in inhibiting the Wnt pathway in previous research.

To evaluate the efficacy of SM08502, researchers generated CSC-enriched tumor spheres from Panc1 cells, a process that eliminates cells lacking stemness. The enriched cultures were then analyzed for stem cell markers, confirming the effectiveness of the enrichment method. The inhibitory effect of SM08502 on spheroid formation and cell viability was compared to that of other known CSC inhibitors, salinomycin and napabucasin.

The results indicated that SM08502 significantly reduced the viability of the enriched Panc1-CSC cells and inhibited spheroid formation more potently than the positive controls. Additionally, it decreased the expression of stemness-related genes such as CD24, LGR4, and VDR. Furthermore, SM08502 treatment significantly impaired the sphere-forming ability of other PC cell lines, suggesting that it is effective against CSCs within these populations.

The study concludes that SM08502 exhibits strong anti-CSC activity against PC and is more potent than other CSC-inhibiting compounds. Its ability to deplete CSCs and reduce stemness could potentially combat relapse and resistance in PC treatment. A phase 1 clinical trial is underway to assess the safety, tolerability, and pharmacokinetics of SM08502 in patients with advanced solid tumors.