{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:15:53Z","timestamp":1789719353257,"version":"4.0.1"},"reference-count":48,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007793","name":"Stiftelsen Kristian Gerhard Jebsen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019729","name":"Centre for Digital Life Norway","doi-asserted-by":"publisher","award":["294916"],"award-info":[{"award-number":["294916"]}],"id":[{"id":"10.13039\/501100019729","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA 213442"],"award-info":[{"award-number":["R01 CA 213442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:p>\n                    Most patients with chronic lymphocytic leukemia (CLL) initially respond to targeted therapies, but eventually relapse and develop resistance. Novel treatment strategies are therefore needed to improve patient outcomes. Here, we performed direct drug testing on primary CLL cells and identified synergy between eight different mitogen\u2010activated protein kinase kinase (MEK) inhibitors and the B\u2010cell lymphoma 2 (Bcl\u20102) antagonist venetoclax. Drug sensitivity was independent of immunoglobulin heavy\u2010chain gene variable region (IGVH) and tumor protein p53 (TP53) mutational status, and CLL cells from idelalisib\u2010resistant patients remained sensitive to the treatment. This suggests that combined MEK\/Bcl\u20102 inhibition may be an option for high\u2010risk CLL. To test whether sensitivity could be detected in other B\u2010cell malignancies, we performed drug testing on cell line models of CLL (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094), multiple myeloma (MM;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098), and mantle cell lymphoma (MCL;\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20097). Like CLL, MM cells were sensitive to the MEK inhibitor trametinib, and synergy was observed with venetoclax. In contrast, MCL cells were unresponsive to MEK inhibition. To investigate the underlying mechanisms of the disease\u2010specific drug sensitivities, we performed flow cytometry\u2010based high\u2010throughput profiling of 31 signaling proteins and regulators of apoptosis in the 19 cell lines. We found that high expression of the antiapoptotic proteins myeloid cell leukemia\u20101 (Mcl\u20101) or B\u2010cell lymphoma\u2010extra large (Bcl\u2010xL) predicted low sensitivity to trametinib\u2009+\u2009venetoclax. The low sensitivity could be overcome by combined treatment with an Mcl\u20101 or Bcl\u2010xL inhibitor. Our findings suggest that MEK\/Bcl\u20102 inhibition has therapeutic potential in leukemia and myeloma, and demonstrate that protein expression levels can serve as predictive biomarkers for treatment sensitivities.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13153","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T12:00:54Z","timestamp":1638532854000},"page":"1153-1170","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mcl\u20101 and Bcl\u2010xL levels predict responsiveness to dual MEK\/Bcl\u20102 inhibition in B\u2010cell malignancies"],"prefix":"10.1002","volume":"16","author":[{"given":"Katrine","family":"Melvold","sequence":"first","affiliation":[{"name":"Department of Cancer Immunology Institute for Cancer Research Oslo University Hospital Norway"},{"name":"K. G. Jebsen Centre for B Cell Malignancies Institute of Clinical Medicine University of Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariaserena","family":"Giliberto","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology Institute for Cancer Research Oslo University Hospital Norway"},{"name":"K. G. Jebsen Centre for B Cell Malignancies Institute of Clinical Medicine University of Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Karlsen","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology Institute for Cancer Research Oslo University Hospital Norway"},{"name":"K. G. Jebsen Centre for B Cell Malignancies Institute of Clinical Medicine University of Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9799-3680","authenticated-orcid":false,"given":"Pilar","family":"Ayuda\u2010Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Centre for Cancer Cell Reprogramming Institute of Clinical Medicine University of Oslo Norway"},{"name":"Department of Molecular Cell Biology Institute for Cancer Research Oslo University Hospital Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hanes","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Centre for Cancer Cell Reprogramming Institute of Clinical Medicine University of Oslo Norway"},{"name":"Department of Molecular Cell Biology Institute for Cancer Research Oslo University Hospital Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2051-5824","authenticated-orcid":false,"given":"Toril","family":"Holien","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine NTNU \u2013 Norwegian University of Science and Technology Trondheim Norway"},{"name":"Department of Immunology and Transfusion Medicine St. Olav\u2019s University Hospital Trondheim Norway"},{"name":"Department of Hematology St. Olav\u2019s University Hospital Trondheim Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorrit","family":"Enserink","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Centre for Cancer Cell Reprogramming Institute of Clinical Medicine University of Oslo Norway"},{"name":"Department of Molecular Cell Biology Institute for Cancer Research Oslo University Hospital Norway"},{"name":"Faculty of Mathematics and Natural Sciences Department of Biosciences University of Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Dana\u2010Farber Cancer Institute Boston MA USA"},{"name":"Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir E.","family":"Tj\u00f8nnfjord","sequence":"additional","affiliation":[{"name":"K. G. Jebsen Centre for B Cell Malignancies Institute of Clinical Medicine University of Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo Norway"},{"name":"Department of Haematology Oslo University Hospital Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-4697","authenticated-orcid":false,"given":"Kjetil","family":"Task\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology Institute for Cancer Research Oslo University Hospital Norway"},{"name":"K. G. Jebsen Centre for B Cell Malignancies Institute of Clinical Medicine University of Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-356X","authenticated-orcid":false,"given":"Sigrid S.","family":"Sk\u00e5nland","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology Institute for Cancer Research Oslo University Hospital Norway"},{"name":"K. G. 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In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10\u201015 and May 17\u201021. 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