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 Kanojia, Lauren Begg, Adrienne M. Orriols, Erica Fleming-Trujillo, Pranathi Vadlamani, Alesia Vialichka, Rosemary Bolin, Jessica N. Perrino, Diane Roth, Matthew R. Clutter, Nicolette A. Zielinski-Mozny, Young Ah Goo, Massimo Cristofanilli, Marc L. Mendillo, Athanassios Vassilopoulos, Dai Horiuchi

Research output: Contribution to journalArticlepeer-review

1 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 languageEnglish
Pages (from-to)358-372.e5
JournalCell Chemical Biology
Volume29
Issue number3
DOIs
StatePublished - Mar 17 2022

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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