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Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis

Cancer Gene Therapy volume 30, pages 1691–1701 (2023)Cite this article

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Abstract

Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.

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Fig. 1: In vitro effects of omipalisib and gedatolisib on OCI-AML3 and THP-1 myeloid leukemia cells.
Fig. 2: Transcriptomic analysis of omipalisib-treated OCI-AML3 cells.
Fig. 3: Omipalisib suppressed oxidative phosphorylation and inhibited mitochondrial biogenesis in OCI-AML3.
Fig. 4: Metabolomic analysis revealed that omipalisib represses amino acids and glutathione metabolism in OCI-AML3.
Fig. 5: Omipalisib suppressed serine biosynthesis and impaired glutathione metabolism.
Fig. 6: Omipalisib impedes the growth of subcutaneous OCI-AML3 xenograft tumors in mice.

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Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary Information files. The RNA-sequencing data generated during this study are posited in the Gene Expression Omnibus (GEO) database (ID: GSE224155).

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Acknowledgements

This study was supported by research grants from the Taiwan Health Foundation, and the Ministry of Science and Technology, Taiwan (MOST 111-2320-B-002-058 and MOST 108-2320-B-002-050-MY3). We acknowledge the technical supports of the Metabolomics Core Laboratory at the Center of Genomic Medicine, National Taiwan University, and the Immune Research Core of the Department of Medical Research at the National Taiwan University Hospital.

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Authors and Affiliations

  1. Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan

    Chi-Yang Tseng, Yu-Hsuan Fu & Liang-In Lin

  2. Graduate Institute of Oncology, National Taiwan University, Taipei, Taiwan

    Da-Liang Ou

  3. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, 2200, Denmark

    Jeng-Wei Lu

  4. The Finsen Laboratory, Rigs Hospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark

    Jeng-Wei Lu

  5. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Hsin-An Hou

  6. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Liang-In Lin

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Contributions

Conceptualization and supervision: L-IL; methodology: C-YT, Y-HF, J-WL; bioinformatics analysis: C-YT, Y-HF; animal experiments: C-YT, D-LO; data curation: C-YT, D-LO; funding acquisition: L-IL. and H-AH; writing—original draft: C-YT; writing—review and editing: L-IL.

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Correspondence to Liang-In Lin.

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Tseng, CY., Fu, YH., Ou, DL. et al. Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis. Cancer Gene Ther 30, 1691–1701 (2023). https://doi.org/10.1038/s41417-023-00675-2

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