Integrative molecular network analysis identifies emergent enzalutamide resistance mechanisms in prostate cancer
Year: 2017
Type: article
Abstract: // 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: [email protected] Joshi J. Alumkal, email: [email protected] 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.
Source: Oncotarget
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Funders: U.S. Department of Defense, American Association for Cancer Research, Prostate Cancer Foundation, University of California, Santa Cruz, Entertainment Industry Foundation, Oregon Health and Science University, Movember Foundation, Prospect Creek Foundation, National Institutes of Health, Oregon Clinical and Translational Research Institute, Stand Up To Cancer, Knight Cancer Institute, Oregon Health and Science University, National Cancer Institute, National Center for Advancing Translational Sciences
Awards: G1581679921, G1868249389, G2148971391, G246298631, G2535433541, G288989767, G3015188539, The Role of LSD1 in the Evolution of Castration Resistant Prostate Cancer, G378425593, G4119534169, G4297529078, IDENTIFYING AND TARGETING MDV3100 RESISTANCE MECHANISMS IN PROSTATE CANCER, G5850682332, Oregon Clinical and Translational Research Institute, G7018417684, G719026130, G8437098882, CLARIFYING MECHANISMS OF BET BROMODOMAIN INHIBITOR RESPONSE IN CASTRATION-RESISTANT PROSTATE CANCER, G8632625050, G9000036658, G9000044262, G9000156400, G977107647
OpenAlex ID: W2769210969