Login to Access Video or Poster Abstract: MP57-19
Sources of Funding: This work is supported in part by grants NIH/NCI This work was supported in part by grants NIH/NCI CA140468, CA168601, CA179970, and DOD PCRP PC150040.

Introduction

Resistance of prostate cancer (CaP) cells to enzalutamide and abiraterone, may be mediated by a multitude of survival signaling pathways. In this study we tested whether AKR1C3 activation and intracrine androgens induce CaP cell resistance to enzalutamide and abiraterone and whether targeting these resistance mechanisms overcomes resistance to enzalutamide and abiraterone and thus improve therapy.

Methods

Global gene expression analysis was analyzed by microarray and transcriptome was analyzed by RNA-seq. Steroid profile including androgens was analyzed by Liquid Chromatography-Mass Spectrometry (LC-MS). The effects of AKR1C3 expression and activation were examined by knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin. The effects of AKR1C3 activation on enzalutamide and abiraterone sensitivity were examined in vitro and in vivo. A Phase I/II clinical trial with enzalutamide plus indomethacin has been designed.

Results

Global gene expression analysis showed that steroid biosynthesis pathway is activated in enzalutamide and abiraterone resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide/abiraterone resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in enzalutamide/abiraterone resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide/abiraterone resistant prostate cancer cells to enzalutamide/abiraterone treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide and abiraterone. Furthermore, the combination of indomethacin and enzalutamide/abiraterone resulted in significant inhibition of enzalutamide and abiraterone-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide/abiraterone resistance. In a Phase I/II combination of indomethacin with enzalutamide trial funded by Department of Defense, patients with mCRPC, good performance status (ECOG 0-2) and vital organ function, and no history of enzalutamide or indomethacin treatment will be recruited. The co-primary objective is to assess the toxicity and prostate-specific antigen (PSA) response (?50% reduction). We will also assess the overall response as determined by the Prostate Cancer Working Group 2 criteria, progression-free survival and molecular correlative studies.

Conclusions

AKR1C3 activation and resulting in an increase in intracrine androgens are critical resistance mechanisms confer resistance to enzalutamide and abiraterone. Targeting AKR1C3 activation may provide a potential treatment strategy for metastatic prostate cancer patients who develop resistance to enzalutamide and abiraterone.

Funding

This work is supported in part by grants NIH/NCI This work was supported in part by grants NIH/NCI CA140468, CA168601, CA179970, and DOD PCRP PC150040.