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Sandy Srinivas, MD
Sandy Srinivas, MD
Posted: Monday, December 5, 2022
Recent findings published in Nature Communications suggest that androgen receptor (AR) signaling inhibitors may fundamentally alter how prostate cancer functions. According to Joshi J. Alumkal, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor, and Zheng Xia, PhD, Oregon Health & Science University, Portland, and colleagues, treatment with the AR inhibitor enzalutamide led a subset of prostate tumors to adapt and become double-negative prostate cancer.
“The greatest unmet need in the clinic right now is understanding the workarounds in a tumor that becomes resistant to AR-targeting drugs, so we can determine how best to treat the patient whose tumor has begun to grow,” Dr. Alumkal explained in an institutional press release. “Our work showed that the majority of the tumors—even after receiving enzalutamide—remain very fuel-dependent, which suggests that continuing to target the androgen receptor could make an enormous difference in these tumors.”
The longitudinal study recruited 21 patients with castration-resistant prostate cancer. The researchers obtained metastatic biopsies before enzalutamide treatment and at the time the tumor became resistant to treatment. Using RNA sequencing, the researchers compared gene expression between the samples, aiming to identify pretreatment and treatment-induced resistance mechanisms.
Sequencing data revealed that in most patients, enzalutamide did not induce marked, sustained changes in the tumor transcriptome from baseline to disease progression. However, three individuals had tumors that became double-negative. Using these samples, the investigators developed a 14-gene signature to predict the risk of lineage plasticity; it included genes linked to the Wnt pathway (RNF43 and TRABD2A), the spliceosome (SNRPF), and the electron transport chain (NDUFA12 and ATP5B). The researchers determined that when applied to two separate patient cohorts, high-risk scores were significantly linked to worse overall survival from the time of treatment with AR-signaling inhibitors (P = .076 and P = .005). This link was also verified in patient-derived xenograft models.
Disclosure: For full disclosures of the study authors, visit nature.org.
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