Application of the CDK9 inhibitor FIT-039 for the treatment of KSHV-associated malignancy

• Published in: BMC cancer Vol. 23; no. 1; p. 71
• Main Authors: Sakamoto, Tetsunori, Ajiro, Masahiko, Watanabe, Akira, Matsushima, Shingo, Ueda, Keiji, Hagiwara, Masatoshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.01.2023; BioMed Central; BMC
• Subjects: Analysis; Antitumor agents; Ascites; B cells; BCBL-1 xenograft; Biotechnology industry; Cancer; Care and treatment; Cell proliferation; Cells; Chemotherapy; Chronic infection; Cyclin-dependent kinase; Cyclin-dependent kinase 9; Cyclin-Dependent Kinase 9 - metabolism; Effusion; Ethylenediaminetetraacetic acid; FIT-039; Gene expression; Genes; Genomes; Health aspects; Herpes viruses; Herpesvirus 8, Human; Humans; Kaposi's sarcoma; Kaposis sarcoma; Kaposi’s sarcoma-associated herpesvirus; Lymphocytes B; Lymphoma; Lymphoma, Primary Effusion - pathology; Lymphomas; Malignancy; Monoclonal antibodies; Mutation; Neoplasms; Patient outcomes; Physiological aspects; Polyclonal antibodies; Primary effusion lymphoma; Reagents; Sarcoma; Sarcoma, Kaposi - drug therapy; Scientific equipment and supplies industry; Vincristine; Xenografts; Japan; United States; United States > US; FIT-039; BCBL-1 xenograft; Cyclin-dependent kinase 9; Kaposi’s sarcoma-associated herpesvirus; Primary effusion lymphoma
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-10540-y

Chronic infection with Kaposi's sarcoma-associated herpes virus (KSHV) in B lymphocytes causes primary effusion lymphoma (PEL), the most aggressive form of KSHV-related cancer, which is resistant to conventional chemotherapy. In this study, we report that the BCBL-1 KSHV PEL cell line does not harbor oncogenic mutations responsible for its aggressive malignancy. Assuming that KSHV viral oncogenes play crucial roles in PEL proliferation, we examined the effect of cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on KSHV viral gene expression and KSHV PEL proliferation. We found that FIT-039 treatment impaired the proliferation of KSHV PEL cells and the expression of KSHV viral genes in vitro. The effects of FIT-039 treatment on PEL cells were further evaluated in the PEL xenograft model that retains a more physiological environment for the growth of PEL growth and KSHV propagation, and we confirmed that FIT-039 administration drastically inhibited PEL growth in vivo. Our current study indicates that FIT-039 is a potential new anticancer drug targeting KSHV for PEL patients.