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Small molecule antagonists to ERG and ILK increase sensitivity of TMPRSS2-ERG prostate cancer cells to enzalutamide Noble, Jake W.


While the introduction of second-generation androgen receptor (AR) pathway inhibitors (ARPIs) have dramatically improved survival of patients with advanced prostate cancer (PC), nearly all men treated with these ARPIs go on to develop resistance. Approximately half of PCs harbour the transmembrane protease, serine 2-erythroblast transformation-specific-related gene (TMPRSS2-ERG) fusion. TMPRSS2 allows the transcription factor ERG to be regulated and expressed by the AR, with ERG driving the transcriptional reprogramming that is hypothesized to transformation and enhance the metastatic potential of these tumours. It may be possible to increase sensitivity of ERG-expressing PCs to ARPIs through co-targeting ERG transcriptional function and ERG-associated proteins like integrin-linked kinase (ILK). Integrin-linked kinase (ILK) is an adaptor and scaffold oncoprotein which is involved in upregulating the PI3K-AKT pathway and epithelial-to-mesenchymal transition. ERG has been shown to upregulate ILK in PC models, and a small molecule antagonist of ILK, QLT-0267, phenocopies aspects of ERG antagonism. We have developed small molecule ERG antagonists, including VPC-18005 that can inhibit ERG binding to DNA, transcriptional activity, and metastatic properties of ERG-expressing PC cells. We hypothesize that VPC-18005 (and some of its analogs and derivatives) and QLT-0267 can increase the sensitivity of ERG-expressing, androgen-responsive PC cells like VCaP cells to enzalutamide-mediated cytotoxicity by further suppressing activity of ERG and ILK that is incompletely eradicated by ARPIs. A series of derivatives and analogs to VPC-18005 were screened using a nano-luciferase inhibition assay; VPC-18156 was selected as the most effective inhibitor of ERG transcription and the lead compound for testing. Proliferation and viability assays, performed through live-cell imaging and fluorescent-activated cell sorting, show that QLT-0267 and VPC-18156 increase sensitivity of VCaP cells to enzalutamide, causing increased cell death. Small interfering RNA against ERG and ILK, used as comparisons to the small-molecule antagonists, are also cooperative with enzalutamide at causing cell death in VCaP cells. Neither VPC-18005 nor VPC-18156 affect AR activity in VCaP cells. VPC-18156 decreases protein expression of a downstream target of ERG, SOX9, in VCaP cells. This project could result in a treatment strategy which can improve the effect of ARPIs in ERG-expressing metastatic castration-resistant PCs.

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