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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 overexpression 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 insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.

SUBMITTER: Galletti G

PROVIDER: S-EPMC4244604 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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ERG induces taxane resistance in castration-resistant prostate cancer.

Galletti Giuseppe G Matov Alexandre A Beltran Himisha H Fontugne Jacqueline J Miguel Mosquera Juan J Cheung Cynthia C MacDonald Theresa Y TY Sung Matthew M O'Toole Sandra S Kench James G JG Suk Chae Sung S Kimovski Dragi D Tagawa Scott T ST Nanus David M DM Rubin Mark A MA Horvath Lisa G LG Giannakakou Paraskevi P Rickman David S DS

Nature communications 20141125

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 overexpression 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 docetax ...[more]

PMID: 25420520

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Project description:Prostate cancer (PC) typically depends on hormones for growth, with androgen deprivation therapy (ADT) serving as the primary treatment. However, many patients progress to a castration-resistant (CR) stage, where their tumor becomes unresponsive to ADT. Despite the common use of conventional chemotherapeutics like taxanes (docetaxel, cabazitaxel), the majority of patients experience recurrence. To uncover the mechanisms underlying the drug-resistant phenotype, we developed docetaxel-resistant CRPC cell lines, and through a drug library screen, we identified MLL-Menin and MLL-WDR5 inhibitors that overcome taxane resistance and significantly induced G2/M arrest and apoptosis. To determine the roles of individual proteins in the MLL complexes, we silenced several MLL partner proteins , and the absence of Menin and LEDGF particularly halted the growth of the resistant cells while showing no significant effect on parentals. Notably, parental cells with Menin silencing failed to develop resistance even after prolonged exposure, unlike their Menin-expressing counterparts, highlighting the critical role of Menin in the resistance process. Menin knockouts were analyzed through RNA-sequencing, and several gene sets, including E2F targets, G2/M checkpoints, and mTORC1 pathways, were found to be negatively regulated in taxane-resistant cells. The ablation of Menin led to a reduction in mTOR levels, and ChIP-qPCR analysis confirmed that Menin was enriched on the mTOR promoter. According to TCGA clinical data, the correlation between MEN1 and mTOR became stronger as the disease advanced to metastatic stages. Furthermore, the combination of the mTOR inhibitor Torin1 and docetaxel enhanced the sensitivity of our resistant cells. Menin deficiency reduced cell proliferation and key expression of cell cycle genes (Cyclin D1, CDK20). Rescue experiments reversed these effects, and Menin showed significant enrichment of the Cyclin D1 and CDK20 promoters. Finally, Menin loss impaired docetaxel resistant CRPC growth in our in vivo model. Our data demonstrate the essentiality of Menin for docetaxel resistance and suggest a combined approach targeting both Menin and mTOR to improve taxane therapy responses. Additionally, Menin regulates some key cell cycle genes to promote the G1/S transition, emphasizing its critical role in cell cycle regulation and the growth of taxane-resistant CRPC.

Project description:Drug resistance in patients remains a significant obstacle to successful treatment, even with improvements in cancer treatment strategies. Resistance to taxanes, such as docetaxel (Dtx) and cabazitaxel (Cbz), frequently emerges in Castration Resistant Prostate Cancer (CR-PCa). Through pulse selection of the parental cells (Du145), we established Dtx- and Cbz-resistant CR-PCa cell models and integrated different omic approaches, including transcriptomics and proteomics, to determine the molecular signatures underlying taxane resistance. Interestingly, several genes were regulated in the same direction (up- or down-regulation) at both the gene and protein expression levels in resistant cells compared to parental cells, suggesting that alterations primarily occur at the transcriptional level and manifest at the protein level. Among the differentially regulated genes, CRIP2, a gene associated with tumor suppressor function, has been found to be the most downregulated in taxane-resistant cells. Conversely, NNMT exhibited top-ranked significant upregulation and has been validated in the context of taxane resistance. Its overexpression was shown to promote taxane resistance, whereas depletion via siRNA or gRNA has resensitized the cells. RNA-sequencing of NNMT-knockout cells has indicated involvement of TGFβ signaling, and suppressing this pathway has further increased the taxane sensitivity. EMT was another pathway depleted upon knockout, and subsequent analysis revealed a significant correlation between NNMT and EMT-related genes (VIM, CDH2, FN1, TGFB1, and ZEB2) in both the cell line panel (CCLE) and patient data. Additionally, in cancers other than PCa, NNMT has been observed to predict treatment outcomes, and notably, among the patients with a high EMT signature, elevated NNMT levels were associated with decreased overall survival. More importantly, NNMT-high patients were found to be non-responders to taxane-containing chemotherapy regimens. Collectively, our findings suggest that targeting NNMT and the pathways it affects, such as TGFβ, offers a viable approach for addressing taxane-resistant PCa.

Dataset Information

ERG induces taxane resistance in castration-resistant prostate cancer.

Publications

ERG induces taxane resistance in castration-resistant prostate cancer.

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