Inhibition of NEK2 Promotes Chemosensitivity and Reduces KSHV-positive Primary Effusion Lymphoma Burden.

Autor:	White MC; Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Wong JP; Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Damania B; Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Microbiology and Immunology, the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Apr 09; Vol. 4 (4), pp. 1024-1040.
DOI:	10.1158/2767-9764.CRC-23-0430
Abstrakt:	Non-Hodgkin lymphoma (NHL) is a common cancer in both men and women and represents a significant cancer burden worldwide. Primary effusion lymphoma (PEL) is a subtype of NHL infected with Kaposi sarcoma-associated herpesvirus (KSHV). PEL is an aggressive and lethal cancer with no current standard of care, owing largely to its propensity to develop resistance to current chemotherapeutic regimens. Here, we report a reliance of KSHV-positive PEL on the mitotic kinase, NEK2, for survival. Inhibition of NEK2 with the inhibitor, JH295, resulted in caspase 3-mediated apoptotic cell death of PEL. Furthermore, NEK2 inhibition significantly prolonged survival and reduced tumor burden in a PEL mouse model. We also demonstrate that the ABC transporter proteins, MDR1 and MRP, are most active in PEL and that inhibition of NEK2 in PEL reduced the expression and activity of these ABC transporter proteins, which are known to mediate drug resistance in cancer. Finally, we report that JH295 treatment sensitized lymphomas to other chemotherapeutic agents such as rapamycin, resulting in enhanced cancer cell death. Overall, these data offer important insight into the mechanisms underlying PEL survival and drug resistance, and suggest that NEK2 is a viable therapeutic target for PEL. Significance: The mitotic kinase, NEK2, is important for the survival of KSHV-positive PEL. NEK2 inhibition resulted in PEL apoptosis and reduced tumor burden in a mouse model. NEK2 inhibition also reduced drug resistance. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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