Abstract 4311: Molecular basis of interaction between ERG and microtubule inhibitors in CRPC patients

Abstract

Abstract Microtubules (MTs) are cytoskeletal polymer of α/β tubulin heterodimers that are involved in several cellular functions including mitosis, cell shape and intracellular trafficking. Due to their fundamental role in the maintenance of cell homeostasis, MTs are the target of several chemotherapeutic drugs that act by either stabilizing (taxanes, epothilones) or destabilizing (vinca alkaloids, Eribulin) the MT network. Taxanes (docetaxel and cabazitaxel) are currently used for first or second line treatment of patients with metastatic castration-resistant prostate caner (CRPC) and are the only class of chemotherapy drugs that improve survival. Despite taxane clinical success, there is significant heterogeneity in how patients respond to taxane therapy and most of CRPC patients eventually become refractory and develop resistance to the treatment. The molecular basis underlying this heterogeneity in treatment response is still to be determined. ERG (ETS-related gene) is over-expressed by 30-80 fold in at least 50% of prostate cancers as a result of gene fusion with the 5′ promoter of the AR-induced TMPRSS2 gene. ERG rearrangement is an early event in prostate cancer tumorigenesis and represents the most frequent recurrent genetic alteration in prostate cancer. We recently showed that ERG over-expression is associated with decreased taxane sensitivity in prostate cancer cell lines, in vivo xenograft models, and in ERG-positive CRPC patients. Mechanistically, we demonstrated that ERG contributes to taxane resistance by binding tubulin in the cytoplasm, altering MT dynamics towards increased catastrophe rate thereby shifting the dynamic equilibrium between MT polymers (preferred taxane substrate) and soluble tubulin dimers (preferred substrate for MT-depolymerizing drugs) towards soluble tubulin. Tiling mutant co-immunoprecipitation showed that ERG-tubulin physical interaction is mediated by ERG PNT domain, which has been also implicated with ERG homo-oligomerization and heterodimerization. Moreover, MT-cosedimentation assay elucidated that ERG predominantly interacts with tubulin dimers instead of MT-polymers. Finally, we demonstrated that treatment with the MT-depolymerizing drugs nocodazole or Eribulin is associated with lack of resistance or even enhanced sensitivity in ERG-positive cells. We are currently investigating the molecular basis of the interaction between Eribulin and ERG in CRPC models, in order to elucidate the potential role of Eribulin in the treatment of ERG+ CRPC patients. Overall, our data strongly suggest a new role for ERG as MT-destabilizing MAP, with significant therapeutic implications in CRPC patients. ERG status could emerge as biomarker predictive of response to MT-inhibitors, driving clinical decisions for patient selection to appropriate therapies. Citation Format: Giuseppe Galletti, Cynthia Cheung, David S. Rickman, Paraskevi Giannakakou. Molecular basis of interaction between ERG and microtubule inhibitors in CRPC patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4311. doi:10.1158/1538-7445.AM2015-4311