演題詳細

シンポジウム / Symposium

【E】シンポジウム1 (Symposium 1 (JSH-ASH Joint Symposium)) : Understanding molecular pathogenesis and biological behavior of MM to further improve its clinical outcome

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日程
2013年10月11日(金)
時間
09:00 - 11:30
会場
第1会場 / Room No.1 (さっぽろ芸文館 1F ニトリ文化ホール)
座長・司会
照井 康仁 (Yasuhito Terui):1、Nikhil C. Munshi:2
1:The Cancer Institute Hospital Of JFCR, Japan、2:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston VA Healthcare System, Harvard Medical School Boston MA, USA
 
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Future therapy for multiple myeloma through therapeutic targeting of cell signaling pathways

演題番号 : SY1-3

黒田 純也 (Junya Kuroda):1

1:Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Japan

 

Multiple myeloma (MM) is a plasma cell malignancy which remains mostly incurable despite major advances in treatment strategies during the past decade. The cell proliferation and survival of myeloma cells are supported by both cell-intrinsic and -extrinsic complex molecular mechanisms. The former include complex and heterogeneous cytogenetic, genetic, epigenetic, and intracellular signaling abnormalities, while the latter are generated by various tumor microenvironmental factors. Activation of RAS/RAF/MEK/MAPK (ERK) and PI3K/AKT signaling pathways in particular is critically important for disease development, maintenance, progression and treatment resistance in MM. Both pathways are activated by tumor microenvironmental factors including cytokines and signals mediated by cell adhesion. Moreover, the RAS/MAPK pathway is activated by cytogenetic/molecular abnormalities, such as t(4;14) translocation, FGFR3 mutation, RAS mutation, or B-Raf mutation, while a few studies have dealt with genomic abnormalities accounting for the activation of the PI3K/AKT pathway. Accordingly, both these pathways constitute therapeutic target candidates, but clinical trials and fundamental studies have demonstrated that the inhibition of RAS, RAF, MEK, PI3K and AKT is of limited efficacy as therapy against MM. This may be because the activities of RAS/MAPK and PI3K/AKT pathways are affected by overlapping and compensative cytogenetic/molecular/microenvironmental abnormalities. Moreover, the degree of addiction of myeloma cells to those pathways varies widely among patients and even among intraclonal subclones in a single patient. Therefore, the search for universal therapeutic target molecule where RAS/AMPK and PI3K/AKT signalings converge is essential for the development of a more effective therapy for MM. RSK2 is a member of the 90 kDa ribosomal S6 kinase family of serine/threonine kinases, and is a downstream mediator of the RAS/MAPK signaling cascade which, in turn, modulates a number of effector molecules for cell proliferation and survival. In addition, RSK2 has been shown to promote PDK1-mediated AKT activation. A recent investigation by us found that the N-terminal kinase domain (NTKD) of RSK2, one of the sites responsible for substrate phosphorylation, is constitutively activated in most MM-derived cell lines and patient-derived primary myeloma cells regardless of the type of cytogenetic abnormalities or upstream molecular signaling. The chemical inhibition of RSK2-NTKD by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-MM effect is accompanied by downregulation of c-MYC, Cyclin D, p21WAF1/CIP1 and MCL1. While cell death induction by lenalidomide (LEN) was partly prevented by interleukin (IL)-6 in NCI-H929 myeloma cells, co-administration of BI-D1870 overcame resistance to LEN induced by IL-6. KMS-11/BTZ cells were highly resistant to bortezomib (BTZ)-induced cell death, but proved to be as sensitive to BI-D1870-induced cell death as were their parental cells. Moreover, BI-D1870 proved to have synergistic or additive effects in combination with upcoming new anti-MM agents such as mTOR inhibitor, HDAC inhibitor and BH3-mimicking inhibitor for BCL2/BCLXL. The therapeutic targeting of PDK1/RSK2 axis as the downstream junction where RAS/MAPK connects with PI3K/AKT signaling may be an attractive and universally applicable candidate target cell for future therapies targeting signaling pathways as a cure for MM with inter-patients diversity and intraclonal heterogeneity.

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