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

Abstract

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.

• Authors: Reiko Isa, Mano Horinaka, Taku Tsukamoto, Kentaro Mizuhara, Yuto Fujibayashi, Yoko Taminishi-Katsuragawa, Haruya Okamoto, Shusuke Yasuda, Yuka Kawaji-Kanayama, Yayoi Matsumura-Kimoto, Shinsuke Mizutani, Yuji Shimura, Masafumi Taniwaki, Toshiyuki Sakai, Junya Kuroda
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 6 (Mar 08 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35328342 (Publication Type: Journal Article)

Chemical References

• 3-Phosphoinositide-Dependent Protein Kinases
• PDPK1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 90-kDa
• STK33 protein, human

Topics

• 3-Phosphoinositide-Dependent Protein Kinases
• Cell Line, Tumor
• Cell Proliferation
• Humans
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribosomal Protein S6 Kinases, 90-kDa (metabolism)