2. Academic Validation
  3. Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors

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

  • Biomed Pharmacother. 2025 Oct 27:192:118689. doi: 10.1016/j.biopha.2025.118689.
Chi-Yang Tseng 1,  Yu-Hsuan Fu 1,  Da-Liang Ou 2,  Hsin-An Hou 3,  Hsiung-Fei Chien 4,  Liang-In Lin 5
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
  • 2 Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan.
  • 3 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 4 Division of Plastic Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan; TMU Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: hfchien@h.tmu.edu.tw.
  • 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: lilin@ntu.edu.tw.
PMID: 41151299 DOI: 10.1016/j.biopha.2025.118689
Abstract

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.

Keywords

Acute myeloid leukemia; Drug resistance; Omipalisib; Phosphoglycerate dehydrogenase inhibitor.

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