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This research was supported by the Breast Cancer Now funding (A.N.T.) at King's College London and the Institute of Cancer Research London, the National Institute for Health Research Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, the US National Institutes of Health grant P30 CA008748 (M.S.) and the Breast Cancer Research Foundation (M.S.). The PDX studies were supported by a 'GHD-pink' research support via the FERO Foundation (VS.). Patient samples and data were provided by King's Health Partners Cancer Biobank, London, UK, which is supported by the Experimental Cancer Medicine Centre at King's College London and the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award. We thank S. Swift, S. Utting and M. Ferrao for technical and administrative assistance, AstraZeneca for providing AZD1208, D. Huszar (AstraZeneca) for providing information on the use of AZD1208, H. Mirza (King's College London) for his support with the bioinformatics analysis, J. Hurst (The Institute of Cancer Research London) for helping with the NanoString nCounter PanCancer Pathway analysis, M. Dowsett (Institute of Cancer Research and Royal Marsden Hospital National Institute for Health Research comprehensive Biomedical Research Centre London) for providing staff and infrastructure support for the NanoString NCounter work, T. Tenev (Institute of Cancer Research) for providing MDA-MB-231 containing the BCL2 pTIPZ overexpression vector and the Guy's Hospital Pharmacy for providing the chemotherapeutic drugs.

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

Publicated to:Nature Medicine. 22 (11): 1303-1313 - 2016-11-01 22(11), DOI: 10.1038/nm.4198

Authors: Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, Plumb DA, Zakka L, Gazinska P, Liccardi G, Meier P, Gris-Oliver A, Cheang MC, Perdrix-Rosell A, Shafat M, Noël E, Patel N, McEachern K, Scaltriti M, Castel P, Noor F, Buus R, Mathew S, Watkins J, Serra V, Marra P, Grigoriadis A, Tutt AN

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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.

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