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MULTIPLE MYELOMA, GAMMOPATHIES

Robust anti-myeloma effect of TAS0612, an RSK/AKT/S6K inhibitor, with venetoclax regardless of cytogenetic abnormalities

Leukemia volume 39, pages 211–221 (2025)Cite this article

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Abstract

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.

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Fig. 1: Molecular and cellular effects of TAS0612 on Human Myeloma Cell Lines.
Fig. 2: Comprehensive gene expression change induced by TAS0612 in HMCLs.
Fig. 3: Molecular effects induced by TAS0612 in HMCLs.
Fig. 4: Ex vivo growth Inhibitory effect of TAS0612 on patient-derived myeloma cells.
Fig. 5: Combinatory effect of TAS0612 and Venetoclax in HMCLs.
Fig. 6: In vivo effect of TAS0612 alone and in combination with VEN against HMCL-xenografted model.

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Data availability

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

Notes

  1. human myeloma cell lines,

  2. 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, yellow tetrazole

  3. Annexin-V

  4. propidium iodide

  5. control

  6. β-actin

  7. standard deviation

  8. Multiple Myeloma Research Foundation

  9. false discovery rate

  10. normal enrichment score

  11. venetoclax

  12. standard error

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Acknowledgements

This work was partly supported by Taiho Pharmaceutical, the Japan Agency for Medical Research and Development (JP19ck0106516h0001, 24ck0106943h0001), JSPS KAKENHI Grant Number 22K08512, the Japanese Society of Hematology Research Grant, the Japan Leukemia Research Fund Award (JK), the Japanese Society for Myeloma Research Award, and a grant-in-aid from the Public Promoting Association Asano Foundation for Studies on Medicine (SM). The authors greatly thank all the participating patients and their families. We thank Ms. Mizushima K and Sakamoto-Inada N for their excellent technical support.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan

    Haruya Okamoto, Shinsuke Mizutani, Taku Tsukamoto, Yoko Katsuragawa-Taminishi, Yuka Kawaji-Kanayama, Kentaro Mizuhara, Ayako Muramatsu, Reiko Isa, Takahiro Fujino, Yuji Shimura & Junya Kuroda

  2. Department of Blood Transfusion, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yuji Shimura

  3. Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan

    Koji Ichikawa

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  1. Haruya Okamoto
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Contributions

H.O. and K.I. performed experiments, analyzed the data, and drafted the manuscript. S.M. assisted and supervised the experiments. Y.K-T., Y.K-K., K.M., A.M., R.I., T.F., T.T., and Y.S. supported experiments and analyzed the data. M.T. K.I. and J.K. designed and supervised the research and drafted the manuscript.

Corresponding author

Correspondence to Junya Kuroda.

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Competing interests

This work is partly supported by Taiho Pharmaceutical Co., Ltd. J.K. is a consultant for Janssen Pharmaceutical, Abbvie, Pfizer, BeiGene, and Bristol-Myers Squibb (BMS), has received research funding from Kyowa Kirin, Chugai Pharmaceutical, Japan Blood Product Organization, Sumitomo Pharmaceutical, Otsuka Pharmaceutical, Asahikasei, and Mochida Pharmaceutical and has received honoraria from Janssen Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, BMS, Novartis, Abbvie, Pfizer, and Astellas Pharmaceutical. S.M. has received honoraria from Sanofi and Ono Pharmaceutical. T.T. has received honoraria from BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, and Chugai Pharmaceutical. T.F. has received honoraria from Takeda Pharmaceutical. Y.S. has received honoraria from Ono Pharmaceutical, BMS, Janssen Pharmaceutical, Sanofi, Kyowa Kirin, Takeda Pharmaceutical, and Chugai Pharmaceutical. K.I. is an employee of Taiho Pharmaceutical.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the institutional review board of Kyoto Prefectural University of Medicine (RBMR-G-124-15). Written informed consent was obtained from all patients for the use of their BM cells. All animal care and treatments were approved by the Institutional Animal Care and Use Committee of Taiho Pharmaceutical Co., Ltd., and all procedures for animal experiments were performed according to the company’s guidelines.

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Okamoto, H., Mizutani, S., Tsukamoto, T. et al. Robust anti-myeloma effect of TAS0612, an RSK/AKT/S6K inhibitor, with venetoclax regardless of cytogenetic abnormalities. Leukemia 39, 211–221 (2025). https://doi.org/10.1038/s41375-024-02439-9

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