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However, acquired resistance limits the long-term efficacy of IO. To elucidate the underlying mechanisms of IO resistance and explore strategies to overcome it, six IO-resistant B-ALL sublines were newly established. Although CD22 expression was preserved in all resistant sublines, more than 80-fold increases in 50% inhibitory concentration (IC50) were observed, accompanied by acquired resistance to IO-induced apoptosis. Microarray analysis revealed upregulation of ABCB1, which was further confirmed by overexpression of the encoded protein, the drug efflux pump P-glycoprotein (P-gp). P-gp inhibition restored IO sensitivity by inhibiting calicheamicin efflux, a key resistance mechanism. Concurrently, poly (ADP-ribose) polymerase (PARP) inhibition of DNA damage repair enhanced IO cytotoxicity. Notably, in the triplet combination of IO with P-gp and PARP inhibitors, PARP inhibition of the repair of DNA damage caused by calicheamicin accumulation following P-gp inhibition markedly enhanced the antitumor effects of IO. This approach may offer a novel and effective therapeutic strategy for IO-resistant B-ALL.<\/jats:p>","DOI":"10.1007\/s12185-026-04221-2","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T16:33:14Z","timestamp":1778517194000},"page":"348-360","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting drug efflux and DNA repair enhances inotuzumab ozogamicin activity in IO-resistant B-ALL cell lines"],"prefix":"10.1007","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7875-2098","authenticated-orcid":false,"given":"Naoko","family":"Ida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Okura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Hosono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Yamauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"issue":"7","key":"4221_CR1","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1002\/ajh.27708","volume":"100","author":"H Kantarjian","year":"2025","unstructured":"Kantarjian H, Jabbour E. 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