Abstract
Purpose: Enzalutamide resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focused on the androgen receptor pathway. In contrast, there is limited information on antiapoptotic mechanisms that may facilitate the treatment resistance. The inhibitor of apoptosis proteins (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here, we examined whether BIRC6, an IAP family member, has a role in enzalutamide resistance of CRPCs and could provide a therapeutic target for enzalutamide-resistant CRPC.Experimental Design: Use of enzalutamide-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived enzalutamide-resistant CRPC tissue xenograft line showing primary enzalutamide resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired enzalutamide resistance. Specific BIRC6 downregulation in these models was produced using a BIRC6-targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qRT-PCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis.Results: Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both enzalutamide-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumor apoptosis without inducing major host toxicity. Pathway enrichment analysis indicated that GPCR and matrisome signaling were the most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of prosurvival genes that were upregulated in the LTL-313BR line.Conclusions:BIRC6 targeting inhibited the growth of enzalutamide-resistant CRPC models and may represent a new option for clinical treatment of advanced, enzalutamide-resistant prostate cancer. Clin Cancer Res; 23(6); 1542-51. ©2016 AACR.
Highlights
Castration-resistant prostate cancer (CRPC) presents a major challenge in the clinical management of advanced prostate cancer
Using a high-fidelity, enzalutamide-resistant, patient-derived castration-resistant prostate cancer (CRPC) tissue xenograft model, we showed that a BIRC6-targeting antisense oligonucleotide (ASO-6w2) effectively suppressed enzalutamideresistant CRPC growth without inducing major host toxicity
In search of a clinically relevant in vivo model for studying the development of enzalutamide-resistant CRPC, we tested a number of our transplantable, patient-derived prostate cancer tissue xenograft lines for enzalutamide sensitivity
Summary
Castration-resistant prostate cancer (CRPC) presents a major challenge in the clinical management of advanced prostate cancer. As most forms of CRPC are still dependent on the androgen receptor (AR) for survival, the advent of new, powerful secondgeneration AR antagonists, such as enzalutamide, has been beneficial for patients with metastatic CRPC [1]. Enzalutamide significantly improves patient survival and has been approved for treating CRPC in post-docetaxel (2012) and pre-docetaxel settings (2014). Treatment with enzalutamide is not curative, and enzalutamide resistance in the clinic has been noted [1, 2]. One fourth of patients showed primary resistance to enzaluta-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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