Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors

Acute myeloid leukemia (AML) is the most common acute leukemia that primarily affects older adults. Dysregulated PI3K/AKT/mTOR signaling pathway is a common abnormality in AML. Our previous study demonstrated the excellent cytotoxicity of dual PI3K/mTOR inhibitor omipalisib against AML cells. However, its clinical application remains challenging because of potential resistance mechanisms following kinase inhibitor administration. In this study, OCI-AML3-OR, an OCI-AML3 subline that is resistant to omipalisib, was established. Transcriptomics analysis revealed that the significant differentially expressed genes (DEGs) between parental and omipalisib-resistant AML cells were dominantly associated with cell cycle-related and nucleotide metabolism pathways. Metabolomic analysis in conjunction with metabolite enrichment analysis revealed a shift in glucose metabolism toward the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP) in OCI-AML3-OR cells. OCI-AML3-OR cells exhibited enhanced proliferation by increasing purine synthesis dominated by SSP and PPP. Targeting phosphoglycerate dehydrogenase (PHGDH), a SSP rate-limiting enzyme, with NCT-503 and WQ-2101 resulted in increased reactive oxygen species levels and the induction of apoptosis in OCI-AML3-OR cells and another omipalisib-insensitive SKNO-1 cell in vitro. Furthermore, we found that, like OCI-AML cells, the exportin 1 (XPO1) inhibitors selinexor and eltanexor significantly induced cell cycle arrest and reduced PHGDH expression in OCI-AML3-OR cells. Finally, in vivo experiments demonstrated that both NCT-503 and selinexor significantly inhibited tumor growth and prolonged mouse survival without causing weight loss of OCI-AML3-OR xenografts. Therefore, treatment with PHGDH inhibitors could be a therapeutic strategy for refractory AML to PI3K/mTOR inhibitors. Relevant clinical trials are warranted.