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In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3K\u03b4 inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V\/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3K\u03b4\/AKT\/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.<\/jats:p>","DOI":"10.3390\/pharmaceutics14102238","type":"journal-article","created":{"date-parts":[[2022,10,21]],"date-time":"2022-10-21T00:34:30Z","timestamp":1666312470000},"page":"2238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Amineh","family":"Ghaderi","sequence":"first","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2137-1428","authenticated-orcid":false,"given":"Mohammad Ali","family":"Okhovat","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Aschan","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Svensson","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitta","family":"Sander","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Schultz","sequence":"additional","affiliation":[{"name":"Kancera AB, Nanna Svartz V\u00e4g 4, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Olin","sequence":"additional","affiliation":[{"name":"Kancera AB, Nanna Svartz V\u00e4g 4, 171 65 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"\u00d6sterborg","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"},{"name":"Department of Hematology, Karolinska University Hospital Solna, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0589-5523","authenticated-orcid":false,"given":"Mohammad","family":"Hojjat-Farsangi","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan","family":"Mellstedt","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital Solna and Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/dvdy.21991","article-title":"Ror-family receptor tyrosine kinases in noncanonical Wnt signaling: Their implications in developmental morphogenesis and human diseases","volume":"239","author":"Minami","year":"2010","journal-title":"Dev. 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