title: PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.
abstract: Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Fara
authors: F
authors: Brasó-Maristany
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Simone
authors: S
authors: Filosto
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Steven
authors: S
authors: Catchpole
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Rebecca
authors: R
authors: Marlow
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.|Cancer Bioinformatics, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors: Jelmar
authors: J
authors: Quist
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Erika
authors: E
authors: Francesch-Domenech
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Darren A
authors: DA
authors: Plumb
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Leila
authors: L
authors: Zakka
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Patrycja
authors: P
authors: Gazinska
authors: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK.
authors: Gianmaria
authors: G
authors: Liccardi
authors: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK.
authors: Pascal
authors: P
authors: Meier
authors: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Albert
authors: 0000-0003-1802-9541
authors: A
authors: Gris-Oliver
authors: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK.
authors: Maggie Chon U
authors: MC
authors: Cheang
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Anna
authors: A
authors: Perdrix-Rosell
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Manar
authors: M
authors: Shafat
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Elodie
authors: E
authors: Noël
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Nirmesh
authors: N
authors: Patel
authors: Oncology iMed, AstraZeneca, Waltham, Massachusetts, USA.
authors: Kristen
authors: K
authors: McEachern
authors: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors: Maurizio
authors: M
authors: Scaltriti
authors: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors: Pau
authors: P
authors: Castel
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Farzana
authors: F
authors: Noor
authors: Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK.
authors: Richard
authors: 0000-0002-3386-3465
authors: R
authors: Buus
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Sumi
authors: S
authors: Mathew
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Johnathan
authors: J
authors: Watkins
authors: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Violeta
authors: V
authors: Serra
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
authors: Pierfrancesco
authors: P
authors: Marra
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.|Cancer Bioinformatics, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors: Anita
authors: A
authors: Grigoriadis
authors: Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.|Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK.
authors: Andrew N
authors: 0000-0001-8715-2901
authors: AN
authors: Tutt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D053778:Thiazolidines / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C587575:AZD1208; C000595707:BCL2 protein, human; D001713:Biphenyl Compounds; C000715470:MAS1 protein, human; C579095:MCL1 protein, human; C489427:MYC protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D053778:Thiazolidines; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1