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.
Highlights
Prostate cancer is the third leading cause of cancerrelated death in the United States [1]
The knowledge that androgens persist in castration-resistant prostate cancer (CRPC) cells and are sufficient to activate androgen receptor (AR) transcriptional activity has led to the development of new therapies to treat patients with CRPC
The secondgeneration AR antagonist enzalutamide is one such example, and two phase III clinical trials demonstrate that enzalutamide improves survival for patients with metastatic CRPC [7, 8]
Summary
Prostate cancer is the third leading cause of cancerrelated death in the United States [1]. Recent work demonstrates that CRPC cells develop resistance to androgen deprivation therapy by synthesizing their own androgens or making use of adrenal androgens to sustain AR function [3, 4, 5] These discoveries led to the development of the novel anti-androgen drug enzalutamide, which competes with androgens for binding to AR and leads to suppression of CRPC tumor growth in pre-clinical models [6]. The prevalence of F876L or other enzalutamide resistance-associated mutations has been reported to occur in approximately 20% of CRPC patients progressing on enzalutamide [13, 14] These mutations are clinically-relevant examples of acquired drug resistance, these mechanisms are currently not targetable by therapeutic compounds. Our approach identified nodes in these subnetworks that may be targeted therapeutically, demonstrating the translational significance of this approach
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