XRP44X, an Inhibitor of Ras/Erk Activation of the Transcription Factor Elk3, Inhibits Tumour Growth and Metastasis in Mice

Abstract

Transcription factors have an important role in cancer but are difficult targets for the development of tumour therapies. These factors include the Ets family, and in this study Elk3 that is activated by Ras oncogene /Erk signalling, and is involved in angiogenesis, malignant progression and epithelial-mesenchymal type processes. We previously described the identification and in-vitro characterisation of an inhibitor of Ras / Erk activation of Elk3 that also affects microtubules, XRP44X. We now report an initial characterisation of the effects of XRP44X in-vivo on tumour growth and metastasis in three preclinical models mouse models, subcutaneous xenografts, intra-cardiac injection-bone metastasis and the TRAMP transgenic mouse model of prostate cancer progression. XRP44X inhibits tumour growth and metastasis, with limited toxicity. Tumours from XRP44X-treated animals have decreased expression of genes containing Elk3-like binding motifs in their promoters, Elk3 protein and phosphorylated Elk3, suggesting that perhaps XRP44X acts in part by inhibiting the activity of Elk3. Further studies are now warranted to develop XRP44X for tumour therapy.

Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway

“…Finally, we tested an inhibitor of ELK3 signaling, XRP44X, in N2a cells Semenchenko et al, 2016). Two hours of inhibition with higher doses of XRP44X showed more potent increases in progranulin levels (Fig.…”

Silencing of ELK3 Induces S-M Phase Arrest and Apoptosis and Upregulates SERPINE1 Expression Reducing Migration in Prostate Cancer Cells

“…ELK3 (also called Net, SAP-2, or ERP) is an ETS domaincontaining transcription factor that forms a ternary complex transcription factor (TCF) together with ELK-1 and serum response factor accessory protein-1 (SAP-1) and binds to a specific DNA sequence through a purine-rich GGA core sequence to regulate the expression of many genes including proto-oncogenes [6,7]. Under basal conditions, ELK3 is a transcriptional repressor, which converts to a transcriptional activator in response to ratsarcoma viral oncogene homolog/ extracellular regulated protein kinases (RAS/ERK) signaling and p38 mitogen-activated protein kinase (MAPK) pathway [8][9][10], and is involved in cell migration, angiogenesis, and malignant progression [11][12][13][14]. Several studies have showed that ELK3 is overexpressed in some cancer cells and correlates with cell migration and invasion [13][14][15].…”

“…Under basal conditions, ELK3 is a transcriptional repressor, which converts to a transcriptional activator in response to ratsarcoma viral oncogene homolog/ extracellular regulated protein kinases (RAS/ERK) signaling and p38 mitogen-activated protein kinase (MAPK) pathway [8][9][10], and is involved in cell migration, angiogenesis, and malignant progression [11][12][13][14]. Several studies have showed that ELK3 is overexpressed in some cancer cells and correlates with cell migration and invasion [13][14][15]. Hypoxiainducible factor-1α (HIF-1α) can regulate the genes related to cell proliferation, apoptosis, angiogenesis, and metastasis, playing an important role in cancer progression [16][17][18].…”

SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

“…The potential value of ELK3 as a target of anticancer drug development is supported by the fact that TNBCs with reduced ELK3 activity completely lost their metastatic characteristics (12). It was shown that small molecule based inhibition of Ras/ERK-mediated ELK3 activity results in the inhibition of prostate cancer progression and metastasis in mice (20). It would be interesting to investigate whether simultaneous inhibition of the TGFβ pathway and ELK3 activity produces clinically effective therapeutic outcomes.…”