Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Inhibition of Tumoral VISTA to Overcome TKI Resistance via Downregulation of the AKT/mTOR and JAK2/STAT5 Pathways in Chronic Myeloid Leukemia

  • Kexin Ai (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Mu Chen (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Zhao Liang (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Xiangyang Ding (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Yang Gao (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Honghao Zhang (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Suwan Wu (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Yanjie He (Department of Hematology, Zhujiang Hospital, Southern Medical University) ;
  • Yuhua Li (Department of Hematology, Zhujiang Hospital, Southern Medical University)
  • Received : 2024.01.22
  • Accepted : 2024.06.10
  • Published : 2024.09.01
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Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

Keywords

Acknowledgement

This research was supported by the the National Natural Science Foundation of China (No. 82270233), Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (No. 2018GZR110105014), The Science and Technology Program of Guangzhou (No. 202201011041) and the National Natural Science Foundation of China (No. U2001224).

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