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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,20]]},"abstract":"<jats:p>\n                    Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2\n                    <jats:sup>+<\/jats:sup>\n                    ) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding\/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2\n                    <jats:sup>+<\/jats:sup>\n                    breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2\n                    <jats:sup>+<\/jats:sup>\n                    human breast tumors. Our in\u00a0vitro and preclinical animal models suggest that activating the MLK3\u2013CD70 axis by the PPP-CNP could sensitize\/overcome trastuzumab resistance in HER2\n                    <jats:sup>+<\/jats:sup>\n                    breast cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2205454119","type":"journal-article","created":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T15:19:20Z","timestamp":1662995960000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2\n                    <sup>+<\/sup>\n                    breast cancer by ceramide-loaded nanoparticles"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2376-6469","authenticated-orcid":false,"given":"Sandeep","family":"Kumar","sequence":"first","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, 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