{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T01:10:22Z","timestamp":1784855422059,"version":"3.55.0"},"reference-count":62,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T00:00:00Z","timestamp":1697328000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K08512"],"award-info":[{"award-number":["22K08512"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>B\u2010cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide\u2010dependent kinase\u20101 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL\u2010derived cell lines examined, including those from activated B\u2010cell\u2010like diffuse large B\u2010cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient\u2010derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.<\/jats:p>","DOI":"10.1111\/cas.15995","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T05:21:52Z","timestamp":1697433712000},"page":"4691-4705","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B\u2010cell lymphomas"],"prefix":"10.1111","volume":"114","author":[{"given":"Yoko","family":"Katsuragawa\u2010Taminishi","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Mizutani","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Kawaji\u2010Kanayama","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7730-9925","authenticated-orcid":false,"given":"Akio","family":"Onishi","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruya","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Isa","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Mizuhara","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Fujino","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6803-5491","authenticated-orcid":false,"given":"Taku","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Shimura","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"},{"name":"Department of Blood Transfusion Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Taniwaki","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Miyagawa\u2010Hayashino","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Konishi","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6130-1550","authenticated-orcid":false,"given":"Junya","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Kyoto Prefectural University of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01620-2"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022015851"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.015"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003535"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.948513"},{"issue":"4","key":"e_1_2_11_7_1","first-page":"965","article-title":"Barriers to achieving a cure in lymphoma","volume":"4","author":"Kambhampati S","year":"2021","journal-title":"Cancer Drug Resist"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2017.04.014"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2015.07.003"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-09-0179"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2017.12.006"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-1420"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.3136"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0605"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23062919"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2011.05.002"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20061088"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0690"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2012.244"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9030746"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-3217"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1593\/tlo.12286"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914018107"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0595"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00133.2017"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30249"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20190105"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-4878-1"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000051"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e32835571be"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02219-8"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23126404"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501520"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-021-03126-6"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11886-023-01845-2"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-020-05618-1"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17064-0"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.06.012"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0628-0"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14920"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2010.531013"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-016-0880-z"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.950571"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2020.1709824"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05081-4"},{"key":"e_1_2_11_47_1","unstructured":"A Study of TAS0612 in Participants With Advanced or Metastatic Solid Tumor Cancer \u2013 Full Text View \u2013 ClinicalTrials.gov.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04586270"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204951"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2017.12.021"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-015-0224-x"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2013.00080"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2015.07.024"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1097-2765(01)00284-2"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.21412"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-010-0395-6"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-022-03469-8"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2018.0380"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14225552"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes8040116"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1462399408000586"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.10.4222"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.01.028"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2021.101089"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.15995","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T20:00:08Z","timestamp":1704484808000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.15995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,15]]},"references-count":62,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1111\/cas.15995"],"URL":"https:\/\/doi.org\/10.1111\/cas.15995","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,15]]},"assertion":[{"value":"2023-05-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}