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

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; Farzana Noor; Richard Buus; Sumi Mathew; Violeta Serra; Pierfrancesco Marra; Anita Grigoriadis; Andrew Tutt

doi:10.1038/nm.4198

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

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 CastelFarzana Noor, Richard Buus, Sumi Mathew, Violeta Serra, Pierfrancesco Marra, Anita Grigoriadis, Andrew Tutt

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

183 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1303-1313
Journal	Nature Medicine
Volume	22
Issue number	11
Early online date	24 Oct 2016
DOIs	https://doi.org/10.1038/nm.4198
Publication status	Published - 1 Nov 2016

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Braso Maristany, F., Filosto, S., Catchpole, S., Marlow, R., Quist, J., Francesch-Domenech, E., Plumb, D. A., Zakka, L., Gazinska, P., Liccardi, G., Meier, P., Gris-Oliver, A., Cheang, M. C. U., Perdrix Rosell, A., Shafat, M., Noel, E., Patel, N., McEachern, K., Scaltriti, M., ... Tutt, A. (2016). PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nature Medicine, 22(11), 1303-1313. https://doi.org/10.1038/nm.4198

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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.",

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

year = "2016",

month = nov,

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doi = "10.1038/nm.4198",

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Braso 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, MCU, Perdrix Rosell, A, Shafat, M, Noel, E , Patel, N, McEachern, K, Scaltriti, M, Castel, P, Noor, F, Buus, R, Mathew, S, Serra, V, Marra, P , Grigoriadis, A & Tutt, A 2016, 'PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer', Nature Medicine, vol. 22, no. 11, pp. 1303-1313. https://doi.org/10.1038/nm.4198

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T1 - PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer

AU - Braso Maristany, Fara

AU - Filosto, Simone

AU - Catchpole, Steven

AU - Marlow, Rebecca

AU - Quist, Jelmar

AU - Francesch-Domenech, Erika

AU - Plumb, Darren A

AU - Zakka, Leila

AU - Gazinska, Patrycja

AU - Liccardi, Gianmaria

AU - Meier, Pascal

AU - Gris-Oliver, Albert

AU - Cheang, Maggie Chon U.

AU - Perdrix Rosell, Anna

AU - Shafat, Manar

AU - Noel, Elodie

AU - Patel, Nirmesh

AU - McEachern, Kristen

AU - Scaltriti, Maurizio

AU - Castel, Pau

AU - Noor, Farzana

AU - Buus, Richard

AU - Mathew, Sumi

AU - Serra, Violeta

AU - Marra, Pierfrancesco

AU - Grigoriadis, Anita

AU - Tutt, Andrew

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

U2 - 10.1038/nm.4198

DO - 10.1038/nm.4198

M3 - Article

SN - 1546-170X

VL - 22

SP - 1303

EP - 1313

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

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

Abstract

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