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

Liying Feng,Xianming Deng,Bing Xu,Yong Zhou,Xihuan Sun,Wei Huang,Yuelong Jiang,Yin Li,Li Li,Kai Chen

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.

Highlights

Double-hit lymphoma (DHL) represents a distinct entity with the acquisition of MYC and BCL-2 or BCL6 translocations, and with a dismal prognosis after standard immunochemotherapy [1]
In the pursuit of small molecules capable of triggering the novel type of cell death that may be useful for the development of therapeutics of current unmet clinic needs, we previously discovered the azaindole derivative, HZX-02-059, as a potent methuosis inducer, which showed both in vitro and in vivo anti-tumor activity against triple-negative breast cancer (TNBC) [14]
We reported that HZX-02-059 could act as a potent cytotoxic anti-tumor agent in DHL cells in vitro and in vivo as well as its molecular mechanisms of cell death induction

Summary

Introduction

Double-hit lymphoma (DHL) represents a distinct entity with the acquisition of MYC and BCL-2 or BCL6 translocations, and with a dismal prognosis after standard immunochemotherapy [1]. The dysregulation of these driving oncogenes confers tumor cells uncontrolled proliferation and disordered cell death [2]. More effective and safe therapeutic approaches for DHL are urgently needed. Whether targeting PIKfyve would act as a potentially useful therapeutic approach for the tough DHL treatment still needs to be elucidated

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