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

doi:10.1016/j.chembiol.2023.10.023

PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

Cell Chem Biol. 2024 Feb 15;31(2):326-337.e11. doi: 10.1016/j.chembiol.2023.10.023. Epub 2023 Nov 27.

Authors

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: warfelna@arizona.edu.
¹⁰ Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH, Frederick, MD 21702, USA. Electronic address: john.brognard@nih.gov.

PMID: 38016478
PMCID: PMC10922308 (available on 2025-02-15)
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.

MeSH terms

Apoptosis
Cell Proliferation
Drug Resistance, Neoplasm*
Humans
Male
Phosphorylation
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / pathology
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-pim-1

Substances

Protein Kinase Inhibitors
PIM1 protein, human
Proto-Oncogene Proteins c-pim-1

Abstract

MeSH terms

Substances

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