Abstract 670: Integrative genomic analysis of alterations driving anti-androgen treatment resistance in vitro
Authors: Dong Shen, Brendan Hodkinson, Deborah Ricci, Karin Verstraeten, Michael Schaffer, Michael Gormley, Shibu Thomas
Journal: Cancer Research (2017)

Abstract Prostate cancer is one of the most frequently diagnosed cancers in the world. It is the second most common type of cancer and the fifth leading cause of cancer death in American men. Enzalutamide (MDV) and apalutamide (ARN-509) are selective competitive antagonists of the androgen receptor (AR). Abiraterone acetate (ABI) is an androgen biosynthesis inhibitor which is used in combination with prednisone in metastatic castration-resistant prostate cancer. Although the anti-androgen and AR inhibitors provide breakthrough treatments of metastatic castration-resistant prostate cancer, approximately a third of patients fail to show PSA response (&amp;gt;50% decline from baseline after 12 weeks of treatment), while another third of patients progress after a few cycles of treatment. Recently, the acquired F876L mutation of the androgen receptor (AR) was identified in advanced prostate cancer cells with acquired resistant to enzalutamide and apalutamide. To systematically identify and understand the mechanisms of resistance, we evaluated 22RV1 and LNCaP prostate cancer cells which were resistant to the treatment of enzalutamide (MDV), apalutamide (ARN-509), and abiraterone acetate (ABI). We isolated the DNA and RNA from both resistant cells and their parent cells. We did RNAseq for gene expression analysis, whole exome sequencing to identify the DNA alterations, and array CGH for copy number change analysis. We confirmed the acquired F876L mutation of the AR identified in LNCaP cells resistant to apalutamide. We identified the novel G644R and R630Q mutations of AR, R213* mutation of TP53, N372H mutation of BRCA1, and E2621G mutation of ATM in LNCaP cells which were resistant to the treatment of enzalutamide and apalutamide. For copy number alterations, we identified acquired copy number gain on chromosome 3, 8, and 18 on 22RV1 resistant cells, and acquired copy number loss on LNCaP resistant cells. Besides acquired DNA alterations, we identified 16 up-regulated and 24 down-regulated genes which are common in both 22RV1 and LNCap cells resistant to enzalutamide and apalutamide. Through pathway enrichment analysis, we identified the Wnt/B-catenin, cAMP signaling, and TREM1 signaling pathways were up-regulated in 22RV1 and LNCap cells resistant to enzalutamide and apalutamide. Detection of acquired genetic alterations in cells resistant to anti-androgen treatment provides us with important insights into the mechanisms of their resistance. Further testing of clinical samples collected at disease progression after treatment with these agents is required to validate these findings. Citation Format: Dong Shen, Brendan Hodkinson, Deborah Ricci, Karin Verstraeten, Michael Schaffer, Michael Gormley, Shibu Thomas. Integrative genomic analysis of alterations driving anti-androgen treatment resistance in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 670. doi:10.1158/1538-7445.AM2017-670