2. Academic Validation
  3. PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

  • Cell Chem Biol. 2023 Nov 16:S2451-9456(23)00384-7. doi: 10.1016/j.chembiol.2023.10.023.
Pedro Torres-Ayuso 1,  Meghri Katerji 2,  Dawid Mehlich 3,  Sophia A Lookingbill 2,  Venkata R Sabbasani 4,  Hope Liou 5,  Andrea L Casillas 6,  Shailender S Chauhan 5,  Remigiusz Serwa 7,  Maxine R Rubin 2,  Anna A Marusiak 8,  Rolf E Swenson 4,  Noel A Warfel 9,  John Brognard 10
Affiliations

Affiliations

  • 1 Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
  • 2 Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA.
  • 3 Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA; Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, 00-783 Warsaw, Poland; Doctoral School of the Medical University of Warsaw, 02-091 Warsaw, Poland.
  • 4 Chemistry and Synthesis Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
  • 5 University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.
  • 6 University of Arizona Cancer Center, Tucson, AZ 85724, USA.
  • 7 ReMedy International Research Agenda Unit, IMol Polish Academy of Sciences, 00-783 Warsaw, Poland.
  • 8 Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, 00-783 Warsaw, Poland.
  • 9 University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA. Electronic address: [email protected].
  • 10 Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA. Electronic address: [email protected].
PMID: 38016478 DOI: 10.1016/j.chembiol.2023.10.023
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.

Keywords

PIM kinases; PROTAC; chemoresistance; prostate cancer; proteolysis; targeted therapeutics.

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