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Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis

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Listed:
  • Xiaofan Sun

    (Jinan University)

  • Yue Li

    (Jinan University)

  • Juan Du

    (Jinan University)

  • Fangshu Liu

    (Jinan University)

  • Caiping Wu

    (Jinan University)

  • Weihao Xiao

    (Jinan University)

  • Guopan Yu

    (Southern Medical University)

  • Xiaowei Chen

    (Guangzhou Medical University)

  • Robert Peter Gale

    (Technology and Medicine)

  • Hui Zeng

    (Southern Medical University)

Abstract

Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.

Suggested Citation

  • Xiaofan Sun & Yue Li & Juan Du & Fangshu Liu & Caiping Wu & Weihao Xiao & Guopan Yu & Xiaowei Chen & Robert Peter Gale & Hui Zeng, 2025. "Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56520-7
    DOI: 10.1038/s41467-025-56520-7
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    1. Peter van Galen & Antonija Kreso & Nathan Mbong & David G. Kent & Timothy Fitzmaurice & Joseph E. Chambers & Stephanie Xie & Elisa Laurenti & Karin Hermans & Kolja Eppert & Stefan J. Marciniak & Jane , 2014. "The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress," Nature, Nature, vol. 510(7504), pages 268-272, June.
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