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.