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In this study, serine\u2010227 (RSK2<jats:sup>Ser227<\/jats:sup>) in the N\u2010terminal kinase domain (NTKD) of RSK2 was found to be ubiquitously active in five MCL\u2010derived cell lines and in tumor tissues derived from five MCL patients. BI\u2010D1870, an inhibitor specific to RSK2\u2010NTKD, caused RSK2<jats:sup>Ser227<\/jats:sup> dephosphorylation, and thereby, induced dose\u2010dependent growth inhibition via G<jats:sub>2<\/jats:sub>\/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\u2010D1870\u2010sensitive cell lines. Comparative gene expression profiling of the MCL\u2010derived cell lines showed that inhibition of RSK2<jats:sup>Ser227<\/jats:sup> by BI\u2010D1870 caused downregulation of oncogenes, such as c\u2010MYC and MYB; anti\u2010apoptosis 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<jats:sup>Ser227<\/jats:sup> enables concomitant blockade of pathways that are critically important in B cell tumorigenesis. In addition, we found favorable combinatory growth inhibitory effects of BI\u2010D1870 with inhibitors of BTK (ibrutinib), AKT (ipatasertib), and BCL2 (venetoclax) in cell characteristic\u2010dependent manners. These results provide a rationale for RSK2<jats:sup>Ser227<\/jats:sup> in the NTKD as a potential therapeutic target in MCL and for future development of a novel bioavailable RSK2 NTKD\u2010specific inhibitor.<\/jats:p>","DOI":"10.1002\/cam4.3136","type":"journal-article","created":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T11:10:49Z","timestamp":1589800249000},"page":"5185-5199","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Serine\u2010227 in the N\u2010terminal kinase domain of RSK2 is a potential therapeutic target for mantle cell lymphoma"],"prefix":"10.1002","volume":"9","author":[{"given":"Yayoi","family":"Matsumura\u2010Kimoto","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology Department of Medicine Kyoto Prefectural University of Medicine Kyoto 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