The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

• Published in: International journal of molecular sciences Vol. 23; no. 6; p. 2919
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.03.2022; MDPI
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Abnormalities; AKT; AKT protein; Apoptosis; BIM protein; Biological effects; Cell cycle; Cell Line, Tumor; Cell Proliferation; Cytogenetics; Enzyme inhibitors; Epigenetics; Gene expression; gene set enrichment analysis; Heterogeneity; Humans; Kinases; mTOR; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; MYC; Myc protein; Patients; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RSK2; TOR protein; Tumors; mTOR; multiple myeloma; AKT; gene set enrichment analysis; MYC; RSK2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23062919

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.