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

Research output: Contribution to journalArticlepeer-review

Fara Braso Maristany, Simone Filosto, Steven Catchpole, Rebecca Marlow, Jelmar Quist, Erika Francesch-Domenech, Darren A Plumb, Leila Zakka, Patrycja Gazinska, Gianmaria Liccardi, Pascal Meier, Albert Gris-Oliver, Maggie Chon U. Cheang, Anna Perdrix Rosell, Manar Shafat, Elodie Noel, Nirmesh Patel, Kristen McEachern, Maurizio Scaltriti, Pau Castel & 7 more Farzana Noor, Richard Buus, Sumi Mathew, Violeta Serra, Pierfrancesco Marra, Anita Grigoriadis, Andrew Tutt

Original languageEnglish
Pages (from-to)1303-1313
JournalNature Medicine
Volume22
Issue number11
Early online date24 Oct 2016
DOIs
Accepted/In press6 Sep 2016
E-pub ahead of print24 Oct 2016
Published1 Nov 2016

King's Authors

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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