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. Epub 2021 Sep 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-pim-1
  • Triple Negative Breast Neoplasms* / metabolism

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim
  • Proteasome Endopeptidase Complex