Pharmacological targeting PIKfyve and tubulin as an effective treatment strategy for double-hit lymphoma

  • Cell Death Discov. 2022 Jan 28;8(1):39. doi: 10.1038/s41420-022-00833-9.
Liying Feng   #  1 ,  Kai Chen   #  2 ,  Wei Huang   #  3 ,  Yuelong Jiang  1 ,  Xihuan Sun  3 ,  Yong Zhou  1 ,  Li Li  3 ,  Yin Li  4 ,  Xianming Deng  5 ,  Bing Xu  6
Affiliations
  • 1. Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, 361003, Xiamen, China.
  • 2. The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun Yat-sen University), 528000, Foshan, Guangdong, China.
  • 3. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361003, Xiamen, China.
  • 4. Department of Oncology, The First Affiliated Hospital of Jinan University, Jinan University, 510630, Guangzhou, China. [email protected].
  • 5. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361003, Xiamen, China. [email protected].
  • 6. Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, 361003, Xiamen, China. [email protected].
  • # Contributed equally.
PMID: 35091546 DOI: 10.1038/s41420-022-00833-9
Abstract

Double-hit lymphoma is one of the most aggressive and refractory lymphoma subtypes with recurrent genetic abnormalities of MYC and Bcl-2 or BCL6 rearrangement, leading to a poor prognosis in the present clinical practice. Therefore, new therapeutic strategies for eliminating double-hit lymphomas are urgently needed. Here, we reported that HZX-02-059, a novel PIKfyve and tubulin dual-target inhibitor, showed a highly cytotoxic activity against double-hit lymphoma cell lines in vitro and in vivo through a noncanonical caspase-independent cell death, methuosis. Mechanistically, the cytotoxicity triggered by HZX-02-059 was contributed to the PIKfyve/TFEB axis-induced cell death of methuosis, as well as the inhibition of tubulin and mTOR/Myc axis-induced cell cycle arrest. In summary, the present findings suggest that HZX-02-059 represents a good starting point for developing targeted therapeutics against double-hit lymphomas.

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