AKR1C3 expression in primary lesion rebiopsy at the time of metastatic castration‐resistant prostate cancer is strongly associated with poor efficacy of abiraterone as a first‐line therapy

Abstract

Background Previous studies had demonstrated that aldo‐keto reductase family 1 member C3 (AKR1C3), a crucial enzyme in the steroidogenic pathway, played an important role in abiraterone (ABI)‐resistance in metastatic castration‐resistant prostate cancer (mCRPC) by increasing intratumoral androgen synthesis. However, its value in predicting treatment response in patients with mCRPC is unknown. Method and Materials Data of 163 patients with metastatic prostate cancer between 2016 and 2018 were retrospectively analyzed. All patients received androgen deprivation therapy plus bicalutamide after initial diagnosis. After mCRPC, either ABI or docetaxel (DOC) treatment was used. No patient had the experience of therapy to the primary tumor. AKR1C3 protein was detected by immunohistochemical staining from rebiopsy (re‐Bx) of primary prostate lesions at mCRPC. Kaplan‐Meier curves and Cox regression were used to analyze the association between AKR1C3 and treatment outcomes. Results AKR1C3 was positive in 58 of 163 (35.6%) cases. AKR1C3 was associated with significantly shorter median prostate‐specific antigen progression‐free survival (mPSA‐PFS, 5.6 mo vs 10.7 mo; P < .001), median radiographic progression‐free survival (mrPFS, 11.1 mo vs 18.0 mo; P = .018), and numerically shorter median overall survival (mOS, 20.4 mo vs 26.4 mo; P = .157). Notably, AKR1C3‐positive patients treated with ABI, but not DOC, had shorter mPSA‐PFS and mrPFS compared with AKR1C3‐negative men, (mPSA‐PFS, 5.7 mo vs. 11.2 mo; P < .001; mrPFS, 12.4 mo vs 23.3 mo; P = .048). However, AKR1C3 expression had no correlation to PSA response or OS. Multivariate Cox regression indicated that AKR1C3 was independently accompanied with rapid PSA progression (hazard ratio [HR], 3.64; 95% confidence interval [CI], 2.10‐6.31; P < 0.001) and radiological progression (HR, 2.08; 95% CI, 1.05‐4.11; P = .036) in the ABI‐treated subgroup. Conclusion This study demonstrated that AKR1C3 detection in tissues from prostate re‐Bx at mCRPC was associated with early resistance to ABI but not DOC. These results will help to make optimal personalized treatment decisions for patients with mCRPC, facilitate physicians predicting the effectiveness of ABI.

The Heterogeneity of Intraductal Carcinoma of the Prostate Is Associated With Different Efficacy of Standard First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer

“…Several biomarkers have been identi ed to guide the treatment decision making for mCRPC patients, e.g. AR-V7, ARK1C3, neuroendocrine differentiation and etc (17)(18)(19). The positivity of these markers indicates poor prognosis in AR-targeting treatment.…”

The AKR1C3/AR‐V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression

“…As both AKR1C3 expression and AR-V7 expression were increased in rebiopsy specimens at mCRPC compared with initial diagnosis in our previous study, 11 we further investigated the correlation between AKR1C3 and AR-V7 in CRPC tissues. As shown in Table 1…”

“…Indeed, AKR1C3 expression in CRPC tissues is strongly associated with poor efficacy of abiraterone as a first-line therapy. 11 In addition, AKR1C3 has been shown to play different roles in mCRPC, such as acting as an EMT driver or AR coactivator. 10,21 Our previous studies revealed that AKR1C3 could act as a novel EMT driver to facilitate PCa metastasis through ERK signalling, which indicated a poor prognosis of patients.…”

“…10 Very recently, we have also demonstrated that AKR1C3 expression in primary lesion rebiopsy at the time of mCRPC is strongly associated with poor efficacy of abiraterone as a first-line therapy. 11 However, the mechanism of increased AKR1C3 leading to the failure of these novel hormonal therapies remains largely unknown.…”

Intracrine androgen biosynthesis and drug resistance

“…Ten or more separate studies have replicated the finding that AKR1C3 is overexpressed in CRPC [38,39,[70][71][72][73]75,76] . One such study showed AKR1C3 overexpression in primary lesion re-biopsies at the time of metastatic disease [77] . Consecutive prostate cancer specimens revealed increased AKR1C3 expression during progression to CRPC [78] .…”