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The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma.
Isa, Reiko; Horinaka, Mano; Tsukamoto, Taku; Mizuhara, Kentaro; Fujibayashi, Yuto; Taminishi-Katsuragawa, Yoko; Okamoto, Haruya; Yasuda, Shusuke; Kawaji-Kanayama, Yuka; Matsumura-Kimoto, Yayoi; Mizutani, Shinsuke; Shimura, Yuji; Taniwaki, Masafumi; Sakai, Toshiyuki; Kuroda, Junya.
Afiliación
  • Isa R; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Horinaka M; Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Tsukamoto T; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Mizuhara K; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Fujibayashi Y; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Taminishi-Katsuragawa Y; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Okamoto H; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Yasuda S; Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Kawaji-Kanayama Y; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Matsumura-Kimoto Y; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Mizutani S; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Shimura Y; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Taniwaki M; Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Sakai T; Center for Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
  • Kuroda J; Department of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Int J Mol Sci ; 23(6)2022 Mar 08.
Article en En | MEDLINE | ID: mdl-35328342
Multiple myeloma (MM) is characterized by remarkable cytogenetic/molecular heterogeneity among patients and intraclonal diversity even in a single patient. We previously demonstrated that PDPK1, the master kinase of series of AGC kinases, is universally active in MM, and plays pivotal roles in cell proliferation and cell survival of myeloma cells regardless of the profiles of cytogenetic and genetic abnormalities. This study investigated the therapeutic efficacy and mechanism of action of dual blockade of two major PDPK1 substrates, RSK2 and AKT, in MM. The combinatory treatment of BI-D1870, an inhibitor for N-terminal kinase domain (NTKD) of RSK2, and ipatasertib, an inhibitor for AKT, showed the additive to synergistic anti-tumor effect on human MM-derived cell lines (HMCLs) with active RSK2-NTKD and AKT, by enhancing apoptotic induction with BIM and BID activation. Moreover, the dual blockade of RSK2 and AKT exerted robust molecular effects on critical gene sets associated with myeloma pathophysiologies, such as those with MYC, mTOR, STK33, ribosomal biogenesis, or cell-extrinsic stimuli of soluble factors, in HMCLs. These results provide the biological and molecular rationales for the dual-targeting strategy for RSK2 and AKT, which may overcome the therapeutic difficulty due to cytogenetic/molecular heterogeneity in MM.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mieloma Múltiple Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Mieloma Múltiple Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Suiza