Gene Sets Linked With Enzalutamide Resistance in Prostate Cancer

By Will Boggs MD

May 26, 2020

NEW YORK (Reuters Health) - The expression of specific gene sets is associated with de novo enzalutamide resistance in men with metastatic castration-resistant prostate cancer (CRPC), according to a new study.

"These results provide greater clarity about pathways that are altered in patients whose tumors do not respond favorably to enzalutamide," Dr. Joshi J. Alumkal of Oregon Health and Science University, in Portland, told Reuters Health by email. "While we do not know for certain which specific pathway may be critical for promoting enzalutamide resistance, several of the pathways we identified are targetable with drugs."

The androgen receptor antagonist enzalutamide improves progression-free and overall survival in men with metastatic CRPC, but as many as half of patients do not respond and the resistance mechanisms are mostly unknown.

Dr. Alumkal and colleagues used transcriptional profiling of metastatic tissue biopsies from 34 men with prostate cancer to identify molecular features associated with de novo resistance to enzalutamide.

The responders and nonresponders did not differ significantly in several genes previously linked to poor outcomes or resistance to androgen receptor (AR)-targeting therapies (TP53, Rb, and PTEN) or in alterations in the AR gene and its expression.

In contrast, gene-set-enrichment analysis identified significant enrichment of 18 pathways in nonresponders versus responders to enzalutamide treatment. Epithelial mesenchymal transition (EMT) was the top gene set activated in nonresponders, but immune hallmark pathways were also activated in nonresponders, the researchers report in PNAS.

AR signaling was not one of the top genes sets differentially activated between nonresponders and responders, but there was a strong trend toward reduced AR activity in nonresponders versus responders.

The findings suggest that low AR transcriptional activity, not AR genomic changes or altered AR expression, might contribute to de novo enzalutamide resistance, the authors say.

There were also differences between responders and nonresponders in neurogenic/stemness programs: a basal lineage was activated in nonresponders to enzalutamide treatment, whereas a luminal lineage program was more activated in responders.

Previous work has also suggested a role of basal lineage in promoting resistance to androgen-deprivation therapy, the authors note.

"Many prior studies had focused on mutations - rather than mRNA expression changes - linked with enzalutamide resistance," Dr. Alumkal said. "Our work with transcriptional profiling sheds additional light and suggests that tumors with an AR activity-low and a stemness program may be particularly resistant to enzalutamide."

"Identifying patients with these tumors and developing more effective therapies that target the bad biology of these tumors will be critical to improve outcomes for this group of patients," he said.

SOURCE: PNAS, online May 18, 2020