ERG induces taxane resistance in castration-resistant prostate cancer

Abstract

Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG over-expression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane in sensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression

“…One well-known feature of AR signaling in prostate cancer involves ERG, which is overexpressed in at least 50% of prostate cancers as a result of gene fusions with genes such as TMPRSS2, SLC45A3, and NDRG1, which have AR promoter regions (27,28). ERG has recently been shown to bind to soluble tubulin in the cytoplasm and antagonize inhibition of microtubule depolymerization by taxanes, resulting in its resistance to this therapy (29). In this paper, we studied LNCaP and LAPC4, hormone-sensitive prostate cancer cell lines, both of which are ERG fusion-negative, and demonstrated that LAPC4, which does not express KDM5D, displayed docetaxel resistance with androgen exposure and also showed the converse, in that blocking AR signaling with enzalutamide sensitized LAPC4 cells to docetaxel.…”

Current treatment strategies for advanced prostate cancer

“…ERG, one of the erythroblast transformation-specific transcription factors, often fuses with the promoter region of the TMPRSS2 gene (21q21.2-3), called TMPRSS2/ERG fusion, and upregulation of the ERG expression level by AR binding to the promoter of TMPRSS2 plays a pivotal role in tumorgenesis with cooperation of other important somatic mutations. 86 Additional effects of ERG overexpression interacting with microtubule dynamics leading to taxane resistance was shown, 87 and detection of TMPRSS2/ERG fusion as a biomarker might have clinical potential for the prediction of taxane sensitivity. 88,89 Mutations in the DNA repair pathway are now intensely focused on the field of cancer research.…”

Exploitation of the Androgen Receptor to Overcome Taxane Resistance in Advanced Prostate Cancer

“…This rearrangement is found in 40-80% of prostate cancers (Clark et al, 2007;Hermans et al, 2006). Recently, ERG was implicated in affecting the shift of microtubules toward instability (Galletti et al, 2014). ERG rearrangements are the most frequently recurring genetic alteration in prostate cancers and are known to undergo gene fusion with the 5 0 promoters of TMPRSS2, SLC45A3, and NDRG1 (Tomlins et al, 2005).…”

“…ERG rearrangements are the most frequently recurring genetic alteration in prostate cancers and are known to undergo gene fusion with the 5 0 promoters of TMPRSS2, SLC45A3, and NDRG1 (Tomlins et al, 2005). Moreover, ERG is able to bind soluble tubulin in the cytoplasm and shift tubulin binding dynamics toward catastrophe contributing to taxane resistance (Galletti et al, 2014). Mutations in the LBD of AR change the binding affinity of the transcription factor for its cytoplasmic-localized ligand.…”