Defeating PIM kinase that promotes tumorigenesis through non-catalytic functions with PROTACs
In brief
Torres-Ayuso et al. found that PIM inhibitors stabilize PIM kinases, which can contribute to prostate cancer growth and therapy resistance via non-catalytic mechanisms. To target non-catalytic PIM functions, a set of PIM degraders was designed. PIM kinase degraders were more efficient at reducing cancer cell viability than catalytic inhibitors
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.
About the Cancer Cell Signaling & Therapeutics Lab
The Cancer Cell Signaling and Therapeutic Lab’s mission is to uncover the molecular drivers of cancers with limited treatment options and translate these discoveries into targeted therapies. By identifying new vulnerabilities in tumor biology, we aim to develop more precise treatments that improve survival while minimizing toxicity. Ultimately, our goal is to deliver therapies that extend and improve the lives of patients facing the greatest unmet needs.
