{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:53:17Z","timestamp":1781585597284,"version":"3.54.5"},"reference-count":39,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"publisher","award":["#6521\u201017"],"award-info":[{"award-number":["#6521\u201017"]}],"id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Diffuse large B\u2010cell lymphoma (DLBCL) remains a challenging disease with limited therapeutic options beyond standard immunochemotherapy. ETS transcription factors, including SPIB and SPI1, are implicated in lymphoma pathogenesis and can be targeted by the small molecule TK216, which disrupts ETS\u2013DHX9 interactions. To explore mechanisms of resistance, we generated stable TK216\u2013resistant clones from the ABC\u2010DLBCL line U2932. Resistant clones exhibited a 4\u20135\u2010fold increase in IC\n                    <jats:sub>50<\/jats:sub>\n                    values and lost the ability to undergo G2\u2013M arrest upon treatment. Transcriptomic and mutational analyses revealed three resistance patterns: (i) MDR1\/ABCB1 overexpression, leading to multidrug efflux; (ii) Cluster A, enriched for proliferation, Wnt, and transcriptional programs, with mutations in ESR2, USP24, and SFSWAP; and (iii) Cluster B, characterized by actin\/microtubule remodeling, altered metabolism, and mutations in SRSF11 and PATJ. Pharmacologic screening revealed an increased sensitivity of resistant cells to BCL2, MCL1, and XPO1 inhibitors, while also showing reduced sensitivity to aurora kinase and microtubule\u2010targeting agents. Venetoclax and selinexor retained activity in resistant models, supporting their potential for rational combinations with TK216. These findings demonstrate that multiple, heterogeneous mechanisms drive resistance to ETS inhibition in DLBCL, highlighting therapeutic strategies to overcome it.\n                  <\/jats:p>","DOI":"10.1002\/cam4.71935","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:26:15Z","timestamp":1778736375000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring Resistance to\n                    <scp>ETS<\/scp>\n                    Targeting Agents in Diffuse Large B\u2010Cell Lymphoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Filippo","family":"Spriano","sequence":"first","affiliation":[{"name":"Institute of Oncology Research, Faculty of Biomedical Sciences USI  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Cascione","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research, 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Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Toretsky","sequence":"additional","affiliation":[{"name":"Departments of Oncology and Pediatrics Lombardi Comprehensive Cancer Center, Georgetown University  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-8983","authenticated-orcid":false,"given":"Francesco","family":"Bertoni","sequence":"additional","affiliation":[{"name":"Institute of Oncology Research, Faculty of Biomedical Sciences USI  Bellinzona Switzerland"},{"name":"Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale  Bellinzona 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