Alectinib and SALL4-Targeted Fatty Acid Oxidation: A Strategy to Combat Oxaliplatin Resistance in Gastric Cancer.

Background/Aims: Oxaliplatin is a frontline chemotherapeutic agent for gastric cancer (GC) patients; yet, its clinical efficacy is often hindered by drug resistance. Recent studies have suggested a link between fatty acid oxidation (FAO) in GC and chemoresistance, but the precise mechanisms remain elusive. Materials and Methods: In this study, SALL4 was identified as a gene that is not only overexpressed in GC but also remarkably enriched in the FAO pathway through differential gene expression screening and gene set enrichment analysis. SALL4 could enhance the FAO process and oxaliplatin resistance in GC, as corroborated by western blot, assessment of FAO rates and adenosine triphosphate levels, and cell counting kit-8. Results: Reversal experiments demonstrated that the small molecule drug Alectinib can counteract the promotion of FAO and oxaliplatin resistance by the upregulation of SALL4. The binding relationship between Alectinib and SALL4 protein was validated through molecular docking simulations and cellular thermal shift assay. Conclusion: This research has brought to light that Alectinib targets SALL4 to modulate the FAO process, thereby reducing the oxaliplatin resistance of GC cells. These findings may open up new avenues to tackle chemoresistance in GC.