Our recent study, published in Nature Communications,1 sheds light on the molecular mechanisms driving this resistance, focusing on how loss of PKCλ/ι, an atypical protein kinase, alters the function of EZH2, an epigenetic regulator. These findings reveal vulnerabilities that we believe can be therapeutically exploited.
We identified PKCλ/ι as a crucial regulator of EZH2, maintaining its canonical role as part of the Polycomb Repressive Complex 2 (PRC2). Under normal conditions, PKCλ/ι phosphorylates EZH2, marking it for degradation via the ubiquitin-proteasome pathway. However, in PKCλ/ι-deficient prostate cancer cells, EZH2 accumulates and shifts to a non-canonical role. This “solo” EZH2 mechanism drives transcriptional activation of the translational machinery, facilitating neuroendocrine prostate cancer (NEPC) features and conferring resistance to ENZA.
Through genome-wide analyses, we demonstrated that loss of PKCλ/ι disrupts the EZH2-H3K27me3 landscape, leading to increased H3K4me3 activation marks. This epigenetic reprogramming fuels protein synthesis and activates the TGF-β pathway. These processes remodel the extracellular matrix and create a tumor-permissive microenvironment, supporting tumor growth and therapy resistance.
Despite its role in resistance, we found that non-canonical EZH2 creates unique vulnerabilities. Pharmacological inhibition of EZH2 effectively restored sensitivity to ENZA in PKCλ/ι-deficient cells. Combining ENZA with EZH2 inhibitors significantly reduced tumor growth in preclinical models, including patient-derived organoids. Additionally, we observed that PKCλ/ι loss heightened reliance on protein translation pathways. Targeting these pathways further sensitized PKCλ/ι-deficient tumors to ENZA, highlighting the therapeutic potential of dual targeting strategies.
Our findings emphasize the importance of molecular profiling in advanced prostate cancer. We propose that patients with PKCλ/ι-deficient tumors could benefit from combination therapies targeting EZH2 and AR signaling pathways. Moreover, TGF-β pathway inhibitors may enhance these strategies, particularly in tumors exhibiting increased translational activity. We also identified potential biomarkers for therapy-resistant disease: high EZH2 expression coupled with low PKCλ/ι levels. These markers could help stratify patients and guide treatment decisions, allowing us to implement more personalized approaches to therapy.
In summary, this study has uncovered critical insights into the mechanisms driving ENZA resistance in CRPC. Our findings highlight non-canonical EZH2 as a driver of lineage plasticity and a therapeutic vulnerability. By targeting the PKCλ/ι-EZH2 axis, we aim to develop more effective and personalized treatments for advanced prostate cancer, offering hope for patients who currently face limited options.
Prostate cancer cells with low expression levels of PKCλ/ι (magenta) accumulate high amounts of nuclear EZH2 (yellow). Credit: Tania Cid-Diaz, PhD. Diaz-Meco Laboratory, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
Written by Maria T. Diaz-Meco1,2 & Jorge Moscat1,2
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
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