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Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3K\u03b2\/\u03b4 inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell\u2013like (ABC) and germinal center B-cell\u2013like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3K\u03b2\/\u03b4 inhibition decreased the pro-survival NF-\u03baB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K\/AKT\/mTOR pathway following PI3K\u03b2\/\u03b4 inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3K\u03b2\/\u03b4 inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3K\u03b2\/\u03b4 signaling and thus identifies a previously unappreciated role of the PI3K\u03b2 isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3K\u03b2\/\u03b4 and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.<\/jats:p>","DOI":"10.1038\/s41375-022-01749-0","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T02:03:03Z","timestamp":1667959383000},"page":"178-189","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["mTOR inhibition amplifies the anti-lymphoma effect of PI3K\u03b2\/\u03b4 blockage in diffuse large B-cell lymphoma"],"prefix":"10.1038","volume":"37","author":[{"given":"Wendan","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Berning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabea","family":"Erdmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Grau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nardjas","family":"Bettazov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myroslav","family":"Zapukhlyak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1705-3638","authenticated-orcid":false,"given":"Fabian","family":"Frontzek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0910-838X","authenticated-orcid":false,"given":"Corinna","family":"Kosnopfel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Grondine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Willis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Klener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Hailfinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8511-0588","authenticated-orcid":false,"given":"Simon T.","family":"Barry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4728-1693","authenticated-orcid":false,"given":"Georg","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,9]]},"reference":[{"key":"1749_CR1","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1056\/NEJMra0807082","volume":"362","author":"G Lenz","year":"2010","unstructured":"Lenz G, Staudt LM. 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Grondine, B.W., J.T.L. and S.T.B. are employees of AstraZeneca. G.L. received research funding from AstraZeneca. G.L. received additional research grants not related to this manuscript from AGIOS, AQUINOX, Bayer, Celgene, Gilead, Janssen, Morphosys, Novartis, Roche, and Verastem. G.L. received honoraria from ADC Therapeutics, Abbvie, Amgen, AstraZeneca, Bayer, BMS, Celgene, Constellation, Genmab, Gilead, Incyte, Janssen, Karyopharm, Morphosys, NanoString, Novartis, and Roche. The remaining authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}