PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.

Autor: Brasó-Maristany F; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Filosto S; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Catchpole S; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Marlow R; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Quist J; 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., Francesch-Domenech E; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Plumb DA; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Zakka L; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Gazinska P; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Liccardi G; Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK., Meier P; Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK., Gris-Oliver A; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Cheang MC; Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK., Perdrix-Rosell A; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Shafat M; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Noël E; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Patel N; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., McEachern K; Oncology iMed, AstraZeneca, Waltham, Massachusetts, USA., Scaltriti M; 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., Castel P; Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York, USA., Noor F; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Buus R; Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, UK., Mathew S; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Watkins J; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Serra V; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Marra P; Breast Cancer Now Research Unit, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK., Grigoriadis A; 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., Tutt AN; 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.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2016 Nov; Vol. 22 (11), pp. 1303-1313. Date of Electronic Publication: 2016 Oct 24.
DOI: 10.1038/nm.4198
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: