Loss, Mutation of NCOR2 Likely Fuels Prostate Cancer Progression, Resistance

By Marilynn Larkin

December 23, 2021

NEW YORK (Reuters Health) - Loss of the NORC2 (nuclear receptor corepressor 2/silencing mediator for retinoid and thyroid hormone receptors) gene could accelerate resistance to androgen deprivation therapy (ADT) in prostate cancer, and novel therapies targeting the gene might overcome treatment resistance, researchers suggest.

"ADT is an excellent targeted therapy for advanced prostate cancer. However, the cancer cells find multiple ways to adapt," Dr. Dominic Smiraglia of Roswell Park Comprehensive Cancer Center in Buffalo, New York, told Reuters Health by email.

"Our (previous) work has demonstrated a clear role for reduced NCOR2 expression to impact the effectiveness of ADT," he said. "Our work now potentially reveals novel mechanisms by which cancer cells are more adaptable to escape therapeutic restraint. By targeting the adaptation process itself, we can avoid playing whack-a-mole trying to target the various adaptions that arise."

"Understanding NCOR2 function will be important to understand how ADT could be combined with epigenetic therapies to reduce chances of (prostate cancer) recurrence," he said.

For the current study, published in Cell Reports, the team analyzed samples from 707 men with nonmetastatic prostate cancer and found that reduced NCOR2 expression was significantly associated with shorter disease-free survival, and with increased concentrations of prostate-specific antigen (PSA), an indicator of progression.

In a subset of 136 men who received ADT, those with higher levels of NCOR2 were significantly less likely than those with lower levels to experience an increase in PSA concentrations.

Subsequent experiments in a mouse model showed that reduced NCOR2 expression after ADT accelerated disease recurrence, and was associated with genetic and epigenetic changes, such as increased DNA hypermethylation, which could make prostate cancer cells more ADT-resistant.

The authors conclude, "These studies reveal robust roles for NCOR2 in regulating the (prostate cancer) transcriptome and epigenome and underscore recent mutational studies linking NCOR2 loss of function to (prostate cancer) disease progression."

Dr. Smiraglia said the team will be looking at how the NCOR2 complex varies by location (i.e., proximal versus distal enhancer sites) and using CRISPR approaches to introduce NCOR2 mutations that are found in advanced disease into early-stage prostate cancer to examine their impact on cell behavior.

Dr. Yung Lyou, a medical oncologist at City of Hope in Duarte, California, commented on the study in an email to Reuters Health, "The main benefit from identifying decreased NCOR2 expression as a mechanism driving ADT failure is that this data can be used as a biomarker to screen for patients who may not respond well to ADT."

"I would like to see a prospective trial using NCOR2 as a biomarker to see if it can predict if prostate cancer patients will develop resistance to the commonly used anti-androgen agents," he said. If NCOR2 can be established as a potential biomarker that can predict which patients would be less likely to benefit from anti-androgen agents (i.e., abiraterone/prednisone, enzalutamide, apalutamide), then we could design a follow up clinical trial to see if the patients with decreased NCOR2 expression could benefit from the use of taxane-based chemotherapy instead."

SOURCE: https://bit.ly/33LwU1T Cell Reports, online December 14, 2021.