2. Academic Validation
  3. Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer

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

  • Cell Chem Biol. 2022 Mar 17;29(3):358-372.e5. doi: 10.1016/j.chembiol.2021.08.011.
Ratika Kunder 1,  Michelle Velyunskiy 2,  Sara F Dunne 3,  Byoung-Kyu Cho 4,  Deepak Kanojia 5,  Lauren Begg 1,  Adrienne M Orriols 6,  Erica Fleming-Trujillo 1,  Pranathi Vadlamani 1,  Alesia Vialichka 1,  Rosemary Bolin 7,  Jessica N Perrino 7,  Diane Roth 1,  Matthew R Clutter 8,  Nicolette A Zielinski-Mozny 9,  Young Ah Goo 10,  Massimo Cristofanilli 11,  Marc L Mendillo 12,  Athanassios Vassilopoulos 13,  Dai Horiuchi 14
Affiliations

Affiliations

  • 1 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 2 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Adlai E. Stevenson High School, Lincolnshire, IL 60069, USA.
  • 3 High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA.
  • 4 Proteomics Center for Excellence, Northwestern University, Chicago, IL 60611, USA.
  • 5 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 6 Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 7 Center for Comparative Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 8 High-Throughput Analysis Laboratory, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 9 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Center for Comparative Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 10 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Proteomics Center for Excellence, Northwestern University, Chicago, IL 60611, USA.
  • 11 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 12 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Simpson Querrey Institute for Epigenetics, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 13 Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 14 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Electronic address: dai.horiuchi@northwestern.edu.
PMID: 34525344 DOI: 10.1016/j.chembiol.2021.08.011
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.

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Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16976
    99.87%, Pim Inhibitor
    Pim
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