title: BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors.
abstract: B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential.
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: K
authors.identifier: http://orcid.org/0000-0001-5009-4509
authors.initials: K
authors.lastname: Korfi
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.affiliation: Core Research Facilities, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Swan
authors.affiliation: Leukemia Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: T C P
authors.initials: TC
authors.lastname: Somervaille
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Dhomen
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: R
authors.identifier: http://orcid.org/0000-0001-7484-4183
authors.initials: R
authors.lastname: Marais
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013864:Thioglycolates / Q000494:pharmacology / Q000627:therapeutic use; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D013864:Thioglycolates; C000592878:UMI-77; D051020:bcl-X Protein; C560077:trametinib; D020930:MAP Kinase Kinase Kinases; C528561:navitoclax