PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

Pedro Torres-Ayuso, Meghri Katerji, Dawid Mehlich, Sophia A. Lookingbill, Venkata R. Sabbasani, Hope Liou, Andrea L. Casillas, Shailender S. Chauhan, Remigiusz Serwa, Maxine R. Rubin, Anna A. Marusiak, Rolf E. Swenson, Noel A. Warfel, John Brognard

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

Original languageEnglish (US)
Pages (from-to)326-337.e11
JournalCell Chemical Biology
Volume31
Issue number2
DOIs
StatePublished - Feb 15 2024

Keywords

  • PIM kinases
  • PROTAC
  • chemoresistance
  • prostate cancer
  • proteolysis
  • targeted therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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