Biomarkers for Predicting Abiraterone Treatment Outcome and Selecting Alternative Therapies in Castration‐Resistant Prostate Cancer

Abstract

Approximately one‐third of patients with metastatic castration‐resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient‐derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan‐CDK inhibitor PHA‐793887. These drugs significantly suppressed the growth of abiraterone‐resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11‐gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.

Mechanistic study of dual‐function inhibitors targeting topoisomerase II and Rad51‐mediated DNA repair pathway against castration‐resistant prostate cancer

“…Although overall survival and progressionfree survival are increased in these ADT treatments, the resistance will be acquired in almost all patients eventually. 3,4 Therefore, there are still unmet medical needs for novel therapies in CRPC treatment.…”

“…Recently, it has been reported that the drug discovery analysis using the L1000 database has discovered mitoxantrone, a topoisomerase II (TOP II) inhibitor, as one of the top potential drug candidates against abiraterone-resistant prostate cancers. 3 Several well-known (e.g., etoposide and doxorubicin) and newly developed TOP II inhibitors have demonstrated potential anti-CRPC activities in both in vitro studies and clinical trials. 3,[6][7][8][9] Notably, it has been reported that cabazitaxel-resistant CRPC cells show higher expression levels of TOP IIα protein than parent CRPC cells.…”

“…3 Several well-known (e.g., etoposide and doxorubicin) and newly developed TOP II inhibitors have demonstrated potential anti-CRPC activities in both in vitro studies and clinical trials. 3,[6][7][8][9] Notably, it has been reported that cabazitaxel-resistant CRPC cells show higher expression levels of TOP IIα protein than parent CRPC cells. Docetaxel-administered tissues and metastatic tumors also demonstrated higher TOP IIα expression levels.…”

“…The cytochrome P450 17A1 inhibitors (e.g., abiraterone acetate) that reduce androgen biosynthesis are the second‐generation ADT in this stage of treatment. Although overall survival and progression‐free survival are increased in these ADT treatments, the resistance will be acquired in almost all patients eventually 3,4 . Therefore, there are still unmet medical needs for novel therapies in CRPC treatment.…”

“…The combination treatment between DDR‐inducing agents and DNA repair inhibitors can be a reasonable strategy against CRPC. Recently, it has been reported that the drug discovery analysis using the L1000 database has discovered mitoxantrone, a topoisomerase II (TOP II) inhibitor, as one of the top potential drug candidates against abiraterone‐resistant prostate cancers 3 . Several well‐known (e.g., etoposide and doxorubicin) and newly developed TOP II inhibitors have demonstrated potential anti‐CRPC activities in both in vitro studies and clinical trials 3,6–9 .…”