Robust anti-myeloma effect of TAS0612, an RSK/AKT/S6K inhibitor, with venetoclax regardless of cytogenetic abnormalities.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
22 Oct 2024
22 Oct 2024
Historique:
received:
24
08
2024
accepted:
10
10
2024
revised:
08
10
2024
medline:
23
10
2024
pubmed:
23
10
2024
entrez:
22
10
2024
Statut:
aheadofprint
Résumé
Multiple myeloma (MM) remains a difficult-to-treat disease even with the latest therapeutic advances due to the complex, overlapping, and heterogeneous cytogenetic, genetic, and molecular abnormalities. To address this challenging problem, we previously identified the universal and critical roles of RSK2 and AKT, the effector signaling molecules downstream of PDPK1, regardless of cytogenetic and genetic profiles. Based on this, in this study, we investigated the anti-myeloma potency of TAS0612, a triple inhibitor against RSK, including RSK2, AKT, and S6K. Treatment with TAS0612 exerted the anti-proliferative effect via cell cycle blockade and the induction of apoptosis in human myeloma-derived cell lines (HMCLs) with diverse cytogenetic and genetic profiles. Ex vivo treatment with TAS0612 also significantly reduced the viability of patient-derived primary myeloma cells with diverse cytogenetic profiles. TAS0612 simultaneously caused the upregulation of several tumor suppressor genes, modulated prognostic genes according to the MMRF CoMMpass data, and downregulated a series of Myc- and mTOR-related genes. Moreover, the combination of TAS0612 with venetoclax (VEN) showed the synergy in inducing apoptosis in HMCLs irrespective of the t(11;14) translocation status. TAS0612 alone and combined with VEN are new potent candidate therapeutic strategies for MM, regardless of cytogenetic/genetic profiles, facilitating its future clinical development.
Identifiants
pubmed: 39438587
doi: 10.1038/s41375-024-02439-9
pii: 10.1038/s41375-024-02439-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Taiho Pharmaceutical (Taiho Pharma)
ID : N.A.
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22K08512
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
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