Citations 1
Association of Wnt pathway activation with prechemotherapy abiraterone acetate resistance in metastatic castration-resistant prostate cancer (mCRPC) by genome-wide analysis of metastases.
Sicotte, Hugues , Ricci, Deborah, Tan, Winston , Costello, Brian A. , Pitot, Henry C., Dronca, Roxana , Ye, Zhenqing , Vedell, Peter T. , Barman, Poulami , Carlson, Rachel E. , Wang, Liewei , Kohli, Manish , Wang, Liguo , Dehm, Scott M. , Hillman, David W. , Gormley, Michael , Bhargava, Vipul , Li, Weimin , Ho, Thai H. , Bryce, Alan H.
Journal of Clinical Oncology | March 29, 2017 | Volume: 35 | Issue: 6_suppl | Pages: 175-175
10.1200/jco.2017.35.6_suppl.175
175 Background: Genome and transcriptome aberrations associated with primary resistance to abiraterone acetate/prednisone (AA/P) in mCRPC are not known. In a prospective trial (NCT#01953640) we assessed whole-exome and RNA-seq based aberrations in metastases of CRPC stage patients (pts) for identifying markers associated with primary resistance to AA/P. Methods: Whole-exome and RNA-seq of biopsies from metastases was performed followed by analyses for association between genomic aberrations & primary resistance. Primary resistance was defined by progression on AA/P after 12-weeks of therapy(non-responders) using PSA, RECIST, bone scan and symptom criteria (per PCWG2). Gene network analysis was performed in genes mutated more frequently in non-responders, and also in genes that were differentially expressed between non-responders and responders and a “risk ratio” (RR) was calculated thereof. Results: Between 6/2013 & 8/2015, 92 pts were enrolled of which 82 had complete whole-exome, RNA-seq and 12-week outcome data available for analysis. Median age was 72.5 yrs (IQR: 68.5-78); median PSA-18 ng/ml (IQR: 8.1- 46.6). At 12-weeks 33/82 had progressed. Using the RR of 2 as threshold, we identified 113 and 292 genes that were more frequently mutated in non-responders & responders respectively. Among the 113 genes, OBSCN, ADAM21, LPHN3, DOCK10 ( P = 0.08, RR= inf) & USP42 ( P = 0.16, RR = 5.71) were the top candidates.Gene network analysis revealed that in non-responders, genes involved in the Wnt/β-catenin pathway were frequently mutated and negative regulators of Wnt pathway ( DKK4, SFRP2 & LRP6) were also frequently deleted. Gene expression analyses revealed the expression levels of Wnt/β-catenin pathway inhibitors were significantly reduced while expression levels of cell cycle regulatory genes were significantly increased in non-responders. Conclusions: In this study we observed Wnt/β-catenin pathway activation to be associated with primary AA/P resistance. This finding offers a potential for the development of predictive biomarkers and modulation of targeted pathways to overcome AA/P resistance. Clinical trial information: NCT# 01953640.