PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer.

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.

• Authors: 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
• Journal: Cell chemical biology (Cell Chem Biol) (Nov 16 2023) ISSN: 2451-9448 [Electronic] United States
• PMID: 38016478 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Ltd.