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Indeed, previous studies in mature T\u2010cell lymphoma (mTCL) cells revealed frequent upregulation of Pim expression. Nevertheless, inhibition of Pim kinases showed only minor effects on the viability of mTCL cells so far. Thus, we here addressed cellular responses to therapeutic inhibition of Pim kinases and identified a PI3K\/Akt\u2010driven activation of mTOR as a significant escape mechanism mitigating the anti\u2010lymphoma effects of Pim inhibition. Indeed, dual inhibition of Pim and PI3 kinases showed synergistic anti\u2010lymphoma effects in\u00a0vitro through downregulation of mTOR\u2010induced protein translation and mitigation of BCL\u2010xL\u2010mediated anti\u2010apoptotic mechanisms. Based on this finding, we next explored the therapeutic potential of the dual Pim\/PI3K inhibitor IBL\u2010202 in mTCL cell lines. Strikingly, IBL\u2010202 strongly induced cell\u2010cycle\u2010dependent cell death in cell lines of different mTCL subtypes. Together, our study provides mechanistic evidence supporting a therapeutic strategy of dual Pim\u2010 and PI3\u2010kinase inhibition in mature T\u2010cell lymphoma.<\/jats:p>","DOI":"10.1111\/ejh.14420","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T22:39:24Z","timestamp":1743547164000},"page":"82-95","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual Targeting of Pim and <scp>PI3<\/scp> Kinases in Mature T\u2010Cell Lymphoma"],"prefix":"10.1111","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7126-3292","authenticated-orcid":false,"given":"M.","family":"Lohrberg","sequence":"first","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Heber","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Ries","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Markus","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Ksionsko","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Nothnick","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Thielking","sequence":"additional","affiliation":[{"name":"Haematology and Medical Oncology University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"O'Neill","sequence":"additional","affiliation":[{"name":"Inflection Biosciences Ltd.  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