Protein kinase B inhibitors enhance the sensitivity of translocated promoter region–fibroblast growth factor receptor 1 cells to fibroblast growth factor receptor 1 inhibitor-induced apoptosis

ObjectiveFibroblast growth factor receptor 1 (FGFR1) inhibitors are considered effective for treating 8p11 myeloproliferative syndrome. However, targeting FGFR1 alone may be inadequate for patients with translocated promoter region (TPR)-FGFR1 rearrangement.MethodsIn this study, we established TPR-FGFR1-expressing BaF3 cells and performed RNA sequencing analysis. Then, western blot analysis was performed to evaluate the protein expression levels of FGFR1 and phosphorylation of protein kinase B. Furthermore, flow cytometric analysis (fluorescence-activated cell sorting) was used to assess apoptosis levels.ResultsRNA sequencing analysis revealed that TPR-FGFR1-related genes are mainly involved in the epidermal growth factor receptor pathway. Gene set enrichment analysis highlighted the enrichment of genes in the phosphoinositide 3-kinase/protein kinase B pathway. FGFR1 inhibitor alone inhibited the phosphorylation of FGFR1 but not that of downstream protein kinase B. Combined FGFR1 inhibitor and protein kinase B inhibitor treatment simultaneously suppressed FGFR1 and protein kinase B phosphorylation. Fluorescence-activated cell sorting showed that combination therapy significantly increased apoptosis levels compared with FGFR1 inhibitor monotherapy.ConclusionsWe found that epidermal growth factor receptor is another activation mechanism of the protein kinase B pathway in TPR-FGFR1-expressing BaF3 cells. Furthermore, co-treatment with FGFR1 inhibitor and protein kinase B inhibitor inhibited the phosphorylation of FGFR1 and protein kinase B. Dual FGFR1 and protein kinase B inhibition enhances apoptosis, supporting dual targeting therapy for TPR-FGFR1-rearranged 8p11 myeloproliferative syndrome, offering a novel treatment direction.