Journal
NATURE MEDICINE
Volume 22, Issue 11, Pages 1303-1313Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4198
Keywords
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Funding
- Breast Cancer Now at King's College London
- Institute of Cancer Research London
- National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London
- US National Institutes of Health [P30 CA008748]
- Breast Cancer Research Foundation
- 'GHD-pink' research via the FERO Foundation
- Experimental Cancer Medicine Centre at King's College London
- Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award
- Biotechnology and Biological Sciences Research Council [BB/L021684/1] Funding Source: researchfish
- Medical Research Council [G1000089, MR/M019217/1] Funding Source: researchfish
- Worldwide Cancer Research [14-1328] Funding Source: researchfish
- BBSRC [BB/L021684/1] Funding Source: UKRI
- MRC [MR/M019217/1, G1000089] Funding Source: UKRI
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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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