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PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

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

  2. Author Address

    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., Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA., 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., Chemistry and Synthesis Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA., University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA., University of Arizona Cancer Center, Tucson, AZ 85724, USA., ReMedy International Research Agenda Unit, IMol Polish Academy of Sciences, 00-783 Warsaw, Poland., Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, 00-783 Warsaw, Poland., University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA. Electronic address: warfelna@arizona.edu., Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA. Electronic address: john.brognard@nih.gov.,
    1. Year: 2023
    2. Date: Nov 16
    3. Epub Date: 2023 11 16
  2. Journal: Cell Chemical Biology
  4. Type of Article: Article
  1. 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. Copyright © 2023. Published by Elsevier Ltd.

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  2. DOI: 10.1016/j.chembiol.2023.10.023
  3. PMID: 38016478
  4. PII : S2451-9456(23)00384-7

Library Notes

  1. Fiscal Year: FY2023-2024
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