RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

Shimura, Yuji; Kuroda, Junya; Ri, Masaki; Nagoshi, Hisao; Yamamoto-Sugitani, Mio; Kobayashi, Tsutomu; Kiyota, Miki; Nakayama, Ryuko; Mizutani, Shinsuke; Chinen, Yoshiaki; Sakamoto, Natsumi; Matsumoto, Yosuke; Horiike, Shigeo; Shiotsu, Yukimasa; Iida, Shinsuke

doi:10.1158/1535-7163.mct-12-0605

Cited by 27 publications

(32 citation statements)

References 48 publications

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“…39 RSK2 has also been shown to directly regulate proteins involved in apoptosis, such as BAD 40,41 and BIM. 16,42 In JJN3 cells, which have among the lowest baseline levels of IKZF1 (and thought to explain their inherent lenalidomide resistance), 8 IRF4 was not substantially downregulated by lenalidomide itself unless an RSK2 inhibitor was added. Unlike lenalidomide, treatment of MM cells with an RSK2 inhibitor alone does not appear to induce IKZF1 and IKZF3 degradation, and thus the mechanism of IRF4 depletion are complementary and nonoverlapping.…”

Section: Discussionmentioning

confidence: 99%

“…BI-D1870 is a selective RSK2 inhibitor previously demonstrated to induce cytotoxicity of myeloma cells through the inhibition of RSK2 activity. 16 Treatment of 4 HMCLs with BI-D1870 alone induced a dose-dependent cytotoxicity (supplemental Figure 4A). When HMCLs were treated with a combination of various doses of BI-D1870 and lenalidomide, a synergistic effect in inducing MM-cell cytotoxicity was observed ( Figure 3A and supplemental Figure 4B).…”

Section: Rsk2 Small Molecule Inhibitors Synergize With Lenalidomide Tmentioning

confidence: 96%

“…18 RSK2 inhibition was reported previously to downregulate MYC, MCL1, and induce BIM expression. 16 In order to understand whether modulation of RSK2 also enhances lenalidomideregulated downstream proteins, western blot analysis was performed on MM cells after RSK2 knockdown or small molecule RSK2 inhibition. RSK2 knockdown and inhibition resulted in a significant reduction of IRF4 or MYC (Figure 6A), in a time-and dose-dependent manner ( Figure 6B-D).…”

Section: Mechanism Of Modulation Of Lenalidomide Sensitivity By Rsk2 mentioning

confidence: 99%

“…30 RSK2 in turn phosphorylates a wide range of substrates, including RSK2, CREB1, and histones. 33,34 Although a previous study demonstrated that oncogenic activation of FGFR3 [via the t(4;14)] in MM phosphorylates and activates RSK2 to induce hematopoietic transformation, 35 a recent study from a different group found that RSK2 is commonly activated in MM cells regardless of type of cytogenetic or upstream molecular signaling, 16 suggesting that RSK2 can be activated by multiple mechanisms in MM and it may be a potential therapeutic target for all MM patients. Consistent with this, we detected phosphorylated RSK2 in all MM cell lines, and we also demonstrated that knockdown of RSK2 or inhibition of RSK2 activity with selective small molecule inhibitors induced cytotoxicity in HMCLs of variable genetic background.…”

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confidence: 99%

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RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Zhu

Yin

Bruins

et al. 2015

Blood

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• High-throughput RNAi screening identified lenalidomide sensitizer genes, including RSK2, RAB, peroxisome, and potassium channel family members.• Knockdown or inhibition of RSK2 synergized with lenalidomide to induce myeloma cytotoxicity and downregulation of interferon regulatory factor 4 and MYC.To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-k-B kinase-a (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-a or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy. (Blood. 2015;125(3): [483][484][485][486][487][488][489][490][491] IntroductionThe immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide are broadly used in the treatment of patients with multiple myeloma (MM) and have produced significant clinical advances in both newly diagnosed and advanced disease.1,2 However, only 30% of relapsed MM patients respond to single agent IMiD therapy and most patients eventually develop drug resistance. The underlying mechanisms defining this nonresponsiveness are largely unknown. Recently, Cereblon (CRBN) and Ikaros/Aiolos (IZKF1 and IZKF3) were identified as the molecular targets of IMiDs in MM 3-6 via their ability to induce cytotoxicity by inhibiting interferon regulatory factor 4 (IRF4) and MYC. The action of IMiDs appears to be mediated via binding to CRBN with activation of its associated E3 ubiquitin ligase and subsequent proteasomal degradation of Ikaros. 5,6 Furthermore, low CRBN and IZKF1 levels are associated with IMiD resistance, 3,4,7,8 but other parallel pathways or downstream events that enhance or preclude drug responsiveness are unknown.In the present study, a druggable genome short interfering RNA (siRNA) screen was used to identify 63 genes whose loss of expression enhance...

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Section: Discussionmentioning

confidence: 99%

Section: Rsk2 Small Molecule Inhibitors Synergize With Lenalidomide Tmentioning

confidence: 96%

Section: Mechanism Of Modulation Of Lenalidomide Sensitivity By Rsk2 mentioning

confidence: 99%

mentioning

confidence: 99%

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RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Zhu

Yin

Bruins

et al. 2015

Blood

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“…We have recently identified that the N-terminal kinase domain (NTKD) of RSK2, which is the most downstream signaling mediator of the RAS/ERK pathway in normal tissues, is universally activated thorough phosphorylation in myeloma cells with diverse cytogenetic/molecular abnormalities, regardless of the activation state of ERK and AKT (25). Importantly, the constitutive activation of RSK2-NTKD is responsible for the regulation of critical molecules for myelomagenesis, including c-MYC or CCNDs; however, the underlying mechanism for RSK2-NTKD in myeloma cells has not been identified (25).…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

et al. 2014

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Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. Cancer Res; 74(24); 7418-29. Ó2014 AACR.

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Serine‐227 in the N‐terminal kinase domain of RSK2 is a potential therapeutic target for mantle cell lymphoma

et al. 2020

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RSK2 is a serine/threonine kinase downstream signaling mediator in the RAS/ERK signaling pathway and may be a therapeutic target in mantle cell lymphoma (MCL), an almost incurable disease subtype of non‐Hodgkin lymphoma. In this study, serine‐227 (RSK2 Ser227 ) in the N‐terminal kinase domain (NTKD) of RSK2 was found to be ubiquitously active in five MCL‐derived cell lines and in tumor tissues derived from five MCL patients. BI‐D1870, an inhibitor specific to RSK2‐NTKD, caused RSK2 Ser227 dephosphorylation, and thereby, induced dose‐dependent growth inhibition via G 2 /M cell cycle blockade and apoptosis in four of the five cell lines, while one cell line showed only modest sensitivity. In addition, RSK2 gene knockdown caused growth inhibition in the four BI‐D1870‐sensitive cell lines. Comparative gene expression profiling of the MCL‐derived cell lines showed that inhibition of RSK2 Ser227 by BI‐D1870 caused downregulation of oncogenes, such as c‐MYC and MYB; anti‐apoptosis genes, such as BCL2 and BCL2L1; genes for B cell development, including IKZF1, IKZF3, and PAX5; and genes constituting the B cell receptor signaling pathway, such as CD19, CD79B, and BLNK. These findings show that targeting of RSK2 Ser227 enables concomitant blockade of pathways that are critically important in B cell tumorigenesis. In addition, we found favorable combinatory growth inhibitory effects of BI‐D1870 with inhibitors of BTK (ibrutinib), AKT (ipatasertib), and BCL2 (venetoclax) in cell characteristic‐dependent manners. These results provide a rationale for RSK2 Ser227 in the NTKD as a potential therapeutic target in MCL and for future development of a novel bioavailable RSK2 NTKD‐specific inhibitor.

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RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

Cited by 27 publications

References 48 publications

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

Serine‐227 in the N‐terminal kinase domain of RSK2 is a potential therapeutic target for mantle cell lymphoma

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