Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer

Abstract

Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but b-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. Significance: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to secondgeneration antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.

Therapy-induced lipid uptake and remodeling underpin ferroptosis hypersensitivity in prostate cancer

“…Extended cell culture (several months) in androgen-depleted or AR antagonized conditions ultimately yielded androgen-independent or Enz-resistant CRPC cells that reinitiated proliferation [6, 8, 34, 35]. Our comparative signature scoring of transcriptomics data sets of relevant studies performed in cell culture leading to Enz resistance in LNCaP and C4-2B cells [26], in castrated mice progressing to primary and secondary CRPC after serial tumor xenograft transplantation of LAPC9 and LNCaP cells [27] and matching PCa tumors from patients before and after androgen deprivation therapy for 22 weeks [28] by GSVA using lipid metabolism related gene sets showed extensive concordance between cell culture models, pre-clinical tumor xenograft models and clinical samples of ATT resistance (Fig. S1C).…”

“…Gene sets of indicated signatures were acquired from Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology, Ingenuity Pathway Analysis, REACTOME and the Molecular Signature Database (hallmark gene sets, Broad Institute). GEO deposited RNAseq data sets GSE104935 [26], GSE88752 [27] and GSE48403 [28] were downloaded as raw counts and processed by an edgeR pipeline with TMM normalization to obtain fragments per kilobase of transcript (fpkm) values. Mean expression was used to collapse multiple isoforms.…”

Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway

“…MEK/ERK and AKT signaling pathways play an important role in treatment resistance to facilitate PCa progression to CRPC [14,24]. Moreover, MAPK/ERK and AKT are well-known drivers of CRPC [13,15], and NSE, an NEPC (neuroendocrine prostate cancer) marker, levels decrease as well (Fig. 5H).…”

“…Chromatin-IP protocols were adapted from previously reported methods [15]. Brie y, cells were crosslinked with 1% formaldehyde at room temperature for 10 minutes and the reaction was quenched by 0.125 M glycine in PBS for 5 minutes at room temperature.…”

“…Herein, we assume that CIgG is a novel factor regulated by the AR-SOX2 signaling pathway. CIgG is associated with the malignant behavior of prostate cancer, and its overexpression induced by ADT can promote the development of CRPC by increasing the activity of MARK/ERK and AKT which are well-established drivers of CRPC [13][14][15][16]. In addition, several lines of evidence have connected the epithelial-to-mesenchymal transition (EMT) to CIgG, Finally, using a Babl/c nude mouse xenograft model, we demonstrate that RP215 inhibits the tumor progression of PCa in vivo.…”