Integrative molecular network analysis identifies emergent enzalutamide resistance mechanisms in prostate cancer

// Carly J. King 1 , Josha Woodward 2 , Jacob Schwartzman 2 , Daniel J. Coleman 2 , Robert Lisac 2 , Nicholas J. Wang 1 , Kathryn Van Hook 2 , Lina Gao 2 , Joshua Urrutia 2 , Mark A. Dane 1 , Laura M. Heiser 1, * and Joshi J. Alumkal 2, * 1 Department of Biomedical Engineering, OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR 97239, USA 2 Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA * These authors have contributed equally to this work Correspondence to: Laura M. Heiser, email: heiserl@ohsu.edu Joshi J. Alumkal, email: alumkalj@ohsu.edu Keywords: prostate cancer; castration resistant; drug resistance; enzalutamide Received: April 13, 2017     Accepted: September 29, 2017     Published: November 20, 2017 ABSTRACT Recent work demonstrates that castration-resistant prostate cancer (CRPC) tumors harbor countless genomic aberrations that control many hallmarks of cancer. While some specific mutations in CRPC may be actionable, many others are not. We hypothesized that genomic aberrations in cancer may operate in concert to promote drug resistance and tumor progression, and that organization of these genomic aberrations into therapeutically targetable pathways may improve our ability to treat CRPC. To identify the molecular underpinnings of enzalutamide-resistant CRPC, we performed transcriptional and copy number profiling studies using paired enzalutamide-sensitive and resistant LNCaP prostate cancer cell lines. Gene networks associated with enzalutamide resistance were revealed by performing an integrative genomic analysis with the PAthway Representation and Analysis by Direct Reference on Graphical Models (PARADIGM) tool. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with MEK, EGFR, RAS, and NFKB. Functional validation studies of 64 genes identified 10 candidate genes whose suppression led to greater effects on cell viability in enzalutamide-resistant cells as compared to sensitive parental cells. Examination of a patient cohort demonstrated that several of our functionally-validated gene hits are deregulated in metastatic CRPC tumor samples, suggesting that they may be clinically relevant therapeutic targets for patients with enzalutamide-resistant CRPC. Altogether, our approach demonstrates the potential of integrative genomic analyses to clarify determinants of drug resistance and rational co-targeting strategies to overcome resistance.