Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer

Ratika Kunder; Michelle Velyunskiy; Sara F. Dunne; Byoung Kyu Cho; Deepak Pritambhai Kanojia; Lauren Begg; Adrienne M. Orriols; Erica Fleming-Trujillo; Pranathi Vadlamani; Alesia Vialichka; Rosemary Bolin; Jessica N. Perrino; Diane Roth; Matthew Ryan Clutter; Nicolette A. Zielinski-Mozny; Young Ah Goo; Massimo Cristofanilli; Marc L. Mendillo; Athanasios Vasilopoulos; Dai Horiuchi

doi:10.1016/j.chembiol.2021.08.011

Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer

Ratika Kunder, Michelle Velyunskiy, Sara F. Dunne, Byoung Kyu Cho, Deepak Pritambhai Kanojia, Lauren Begg, Adrienne M. Orriols, Erica Fleming-Trujillo, Pranathi Vadlamani, Alesia Vialichka, Rosemary Bolin, Jessica N. Perrino, Diane Roth, Matthew Ryan Clutter, Nicolette A. Zielinski-Mozny, Young Ah Goo, Massimo Cristofanilli, Marc L. Mendillo, Athanasios Vasilopoulos, Dai Horiuchi^*

^*Corresponding author for this work

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

11 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations.

Original language	English (US)
Pages (from-to)	358-372.e5
Journal	Cell Chemical Biology
Volume	29
Issue number	3
DOIs	https://doi.org/10.1016/j.chembiol.2021.08.011
State	Published - Mar 17 2022

Funding

We acknowledge the following support: US Department of Defense Breast Cancer Research Program (W81XWH1810053 to D.H.), Susan G. Komen Foundation (CCR17488145 to M.L.M, CCR16376693 to D.H.), the Lynn Sage Foundation (M.L.M. A. Vassilopoulos, D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.K. M.C. and D.H.), the Northwestern Medicine Catalyst Funds (D.H.), and the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the National Institutes of Health's National Center for Advancing Translational Sciences (UL1TR001422). Drug combination screens were carried out at the Northwestern High Throughput Analysis Core, which received support from a National Cancer Institute Cancer Center Support Grant (NCI CA060553). The mass spectrometry experiments were carried out at the Northwestern Proteomics Core Facility, generously supported by the National Cancer Institute CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from the National Institutes of Health Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract was created with BioRender.com. R.K. S.D. D.R. M.R.C. N.A.Z. Y.G. M.C. M.L.M, A. Vassilopoulos, and D.H. designed the research. R.K. M.V. S.D. D.K. B.C. L.B. A.M.O. E.F. P.V. R.B. J.N.P. A. Vialichka, M.R.C. and D.H. performed the research. R.K. M.V. S.D. B.C. L.B. A.M.O. E.F. P.V. M.R.C. Y.G. M.L.M, A. Vassilopoulos, and D.H. analyzed the data. R.K. M.V. B.C. L.B. A.M.O. Y.G. M.L.M. A. Vassilopoulos, and D.H. wrote the paper. D.H. supervised the study. The authors declare no competing interest. We acknowledge the following support: US Department of Defense Breast Cancer Research Program ( W81XWH1810053 to D.H.), Susan G. Komen Foundation ( CCR17488145 to M.L.M, CCR16376693 to D.H.), the Lynn Sage Foundation (M.L.M., A. Vassilopoulos, D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.K., M.C., and D.H.), the Northwestern Medicine Catalyst Funds (D.H.), and the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the National Institutes of Health 's National Center for Advancing Translational Sciences ( UL1TR001422 ). Drug combination screens were carried out at the Northwestern High Throughput Analysis Core, which received support from a National Cancer Institute Cancer Center Support Grant ( NCI CA060553 ). The mass spectrometry experiments were carried out at the Northwestern Proteomics Core Facility, generously supported by the National Cancer Institute CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award ( S10OD025194 ) from the National Institutes of Health Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 . The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract was created with BioRender.com .

Keywords

MYC oncoprotein
PIM kinase inhibitor
Triple-negative breast cancer
chemical genetics
proteasome inhibitors
protein homeostasis
proteotoxic stress
rational combination therapy

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2021.08.011

Cite this

Kunder, R., Velyunskiy, M., Dunne, S. F., Cho, B. K., Kanojia, D. P., Begg, L., Orriols, A. M., Fleming-Trujillo, E., Vadlamani, P., Vialichka, A., Bolin, R., Perrino, J. N., Roth, D., Clutter, M. R., Zielinski-Mozny, N. A., Goo, Y. A., Cristofanilli, M., Mendillo, M. L., Vasilopoulos, A., & Horiuchi, D. (2022). Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer. Cell Chemical Biology, 29(3), 358-372.e5. https://doi.org/10.1016/j.chembiol.2021.08.011

@article{7a940305f2ff453cb35f03f7f7c60060,

title = "Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer",

abstract = "Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations.",

keywords = "MYC oncoprotein, PIM kinase inhibitor, Triple-negative breast cancer, chemical genetics, proteasome inhibitors, protein homeostasis, proteotoxic stress, rational combination therapy",

author = "Ratika Kunder and Michelle Velyunskiy and Dunne, {Sara F.} and Cho, {Byoung Kyu} and Kanojia, {Deepak Pritambhai} and Lauren Begg and Orriols, {Adrienne M.} and Erica Fleming-Trujillo and Pranathi Vadlamani and Alesia Vialichka and Rosemary Bolin and Perrino, {Jessica N.} and Diane Roth and Clutter, {Matthew Ryan} and Zielinski-Mozny, {Nicolette A.} and Goo, {Young Ah} and Massimo Cristofanilli and Mendillo, {Marc L.} and Athanasios Vasilopoulos and Dai Horiuchi",

note = "Funding Information: We acknowledge the following support: US Department of Defense Breast Cancer Research Program (W81XWH1810053 to D.H.), Susan G. Komen Foundation (CCR17488145 to M.L.M, CCR16376693 to D.H.), the Lynn Sage Foundation (M.L.M. A. Vassilopoulos, D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.K. M.C. and D.H.), the Northwestern Medicine Catalyst Funds (D.H.), and the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the National Institutes of Health's National Center for Advancing Translational Sciences (UL1TR001422). Drug combination screens were carried out at the Northwestern High Throughput Analysis Core, which received support from a National Cancer Institute Cancer Center Support Grant (NCI CA060553). The mass spectrometry experiments were carried out at the Northwestern Proteomics Core Facility, generously supported by the National Cancer Institute CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from the National Institutes of Health Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract was created with BioRender.com. R.K. S.D. D.R. M.R.C. N.A.Z. Y.G. M.C. M.L.M, A. Vassilopoulos, and D.H. designed the research. R.K. M.V. S.D. D.K. B.C. L.B. A.M.O. E.F. P.V. R.B. J.N.P. A. Vialichka, M.R.C. and D.H. performed the research. R.K. M.V. S.D. B.C. L.B. A.M.O. E.F. P.V. M.R.C. Y.G. M.L.M, A. Vassilopoulos, and D.H. analyzed the data. R.K. M.V. B.C. L.B. A.M.O. Y.G. M.L.M. A. Vassilopoulos, and D.H. wrote the paper. D.H. supervised the study. The authors declare no competing interest. Funding Information: We acknowledge the following support: US Department of Defense Breast Cancer Research Program ( W81XWH1810053 to D.H.), Susan G. Komen Foundation ( CCR17488145 to M.L.M, CCR16376693 to D.H.), the Lynn Sage Foundation (M.L.M., A. Vassilopoulos, D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.K., M.C., and D.H.), the Northwestern Medicine Catalyst Funds (D.H.), and the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the National Institutes of Health 's National Center for Advancing Translational Sciences ( UL1TR001422 ). Drug combination screens were carried out at the Northwestern High Throughput Analysis Core, which received support from a National Cancer Institute Cancer Center Support Grant ( NCI CA060553 ). The mass spectrometry experiments were carried out at the Northwestern Proteomics Core Facility, generously supported by the National Cancer Institute CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award ( S10OD025194 ) from the National Institutes of Health Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 . The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract was created with BioRender.com . Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2022",

month = mar,

day = "17",

doi = "10.1016/j.chembiol.2021.08.011",

language = "English (US)",

volume = "29",

pages = "358--372.e5",

journal = "Cell Chemical Biology",

issn = "2451-9456",

publisher = "Elsevier Inc.",

number = "3",

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Kunder, R, Velyunskiy, M, Dunne, SF, Cho, BK, Kanojia, DP, Begg, L, Orriols, AM, Fleming-Trujillo, E, Vadlamani, P, Vialichka, A, Bolin, R, Perrino, JN, Roth, D, Clutter, MR, Zielinski-Mozny, NA, Goo, YA, Cristofanilli, M, Mendillo, ML, Vasilopoulos, A & Horiuchi, D 2022, 'Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer', Cell Chemical Biology, vol. 29, no. 3, pp. 358-372.e5. https://doi.org/10.1016/j.chembiol.2021.08.011

TY - JOUR

T1 - Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer

AU - Kunder, Ratika

AU - Velyunskiy, Michelle

AU - Dunne, Sara F.

AU - Cho, Byoung Kyu

AU - Kanojia, Deepak Pritambhai

AU - Begg, Lauren

AU - Orriols, Adrienne M.

AU - Fleming-Trujillo, Erica

AU - Vadlamani, Pranathi

AU - Vialichka, Alesia

AU - Bolin, Rosemary

AU - Perrino, Jessica N.

AU - Roth, Diane

AU - Clutter, Matthew Ryan

AU - Zielinski-Mozny, Nicolette A.

AU - Goo, Young Ah

AU - Cristofanilli, Massimo

AU - Mendillo, Marc L.

AU - Vasilopoulos, Athanasios

AU - Horiuchi, Dai

N1 - Funding Information: We acknowledge the following support: US Department of Defense Breast Cancer Research Program (W81XWH1810053 to D.H.), Susan G. Komen Foundation (CCR17488145 to M.L.M, CCR16376693 to D.H.), the Lynn Sage Foundation (M.L.M. A. Vassilopoulos, D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.K. M.C. and D.H.), the Northwestern Medicine Catalyst Funds (D.H.), and the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the National Institutes of Health's National Center for Advancing Translational Sciences (UL1TR001422). Drug combination screens were carried out at the Northwestern High Throughput Analysis Core, which received support from a National Cancer Institute Cancer Center Support Grant (NCI CA060553). The mass spectrometry experiments were carried out at the Northwestern Proteomics Core Facility, generously supported by the National Cancer Institute CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from the National Institutes of Health Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract was created with BioRender.com. R.K. S.D. D.R. M.R.C. N.A.Z. Y.G. M.C. M.L.M, A. Vassilopoulos, and D.H. designed the research. R.K. M.V. S.D. D.K. B.C. L.B. A.M.O. E.F. P.V. R.B. J.N.P. A. Vialichka, M.R.C. and D.H. performed the research. R.K. M.V. S.D. B.C. L.B. A.M.O. E.F. P.V. M.R.C. Y.G. M.L.M, A. Vassilopoulos, and D.H. analyzed the data. R.K. M.V. B.C. L.B. A.M.O. Y.G. M.L.M. A. Vassilopoulos, and D.H. wrote the paper. D.H. supervised the study. The authors declare no competing interest. Funding Information: We acknowledge the following support: US Department of Defense Breast Cancer Research Program ( W81XWH1810053 to D.H.), Susan G. Komen Foundation ( CCR17488145 to M.L.M, CCR16376693 to D.H.), the Lynn Sage Foundation (M.L.M., A. Vassilopoulos, D.H.), the Translational Bridge Program of Robert H. Lurie Comprehensive Cancer Center of Northwestern University (R.K., M.C., and D.H.), the Northwestern Medicine Catalyst Funds (D.H.), and the Northwestern University Clinical and Translational Sciences Institute (D.H.), which was supported by the National Institutes of Health 's National Center for Advancing Translational Sciences ( UL1TR001422 ). Drug combination screens were carried out at the Northwestern High Throughput Analysis Core, which received support from a National Cancer Institute Cancer Center Support Grant ( NCI CA060553 ). The mass spectrometry experiments were carried out at the Northwestern Proteomics Core Facility, generously supported by the National Cancer Institute CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award ( S10OD025194 ) from the National Institutes of Health Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 . The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract was created with BioRender.com . Publisher Copyright: © 2021 Elsevier Ltd

PY - 2022/3/17

Y1 - 2022/3/17

N2 - Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations.

AB - Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations.

KW - MYC oncoprotein

KW - PIM kinase inhibitor

KW - Triple-negative breast cancer

KW - chemical genetics

KW - proteasome inhibitors

KW - protein homeostasis

KW - proteotoxic stress

KW - rational combination therapy

UR - http://www.scopus.com/inward/record.url?scp=85126268035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85126268035&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2021.08.011

DO - 10.1016/j.chembiol.2021.08.011

M3 - Article

C2 - 34525344

AN - SCOPUS:85126268035

SN - 2451-9456

VL - 29

SP - 358-372.e5

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 3

ER -

Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer

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UN SDGs

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