Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

Abstract

Background: EPH (erythropoietin-producing hepatocellular) receptors are clinically relevant targets in several malignancies. This report describes the effects of GLPG1790, a new potent pan-EPH inhibitor, in human embryonal rhabdomyosarcoma (ERMS) cell lines.

Antitumorigenic Effects of Inhibiting Ephrin Receptor Kinase Signaling by GLPG1790 against Colorectal Cancer Cell Lines In Vitro and In Vivo

“…Interestingly, the Ephs are among the few receptor tyrosine kinases known to negatively regulate RAS signaling and its downstream pathways in a variety of cell types [39] though, under some circumstances, Eph receptors activate, rather than inhibit MAPK signaling [40]. We also have shown in previous reports that GLPG1790 induces irreversible growth arrest and differentiation by downregulating ERK in RMS cells [11]. Herein, GLPG1790 strongly and persistently increased the phosphorylation/ activation of ERK signaling in HCT116 cells indicating that relationship between RAS and Eph signaling is similar to that of RMS cells.…”

“…Unexpectedly, GLPG1790 enhanced expression of cyclin D1, known to be a positive regulator of the G 1 /S cell-cycle transition [28]. We have recently shown that GLPG1790 upregulates the expression of cyclin D1 in RMS, inducing the cytoplasmatic/perinuclear accumulation of the protein [11]. Reports have shown that this accumulation correlates with a lower proliferative index in several cancer types [29,30].…”

“…CRC cells express high levels of different Eph proteins including EphA2, a known marker of poor prognosis in advanced CRC and a potentially critical therapeutic target for the treatment of CRC [7][8][9]. We have recently shown the anticancer proprieties of GLPG1790, a new pan inhibitor of the Eph receptors with a strong efficiency versus EphA2, versus several breast, rhabdomyosarcoma, and glioblastoma cell lines, both in vitro and in vivo [10][11][12]. Since our preliminary in vitro investigation showed the therapeutic potential of GLPG1790 also versus CRC [13], we decided to better characterize the pharmacological action of this drug on CRC by using in vitro and in vivo approaches on p53 wild-type or mutated CRC cell lines.…”

“…We have recently developed a preclinical, orally bioavailable small molecule named GLPG1790 that is able to inhibit, at nanomolar concentrations, the activity of various Eph receptors, with a particularly strong efficiency versus EphA2 [10]. e molecule to efficiently diminishes the phenotypic transformation of several breast, rhabdomyosarcoma, and glioblastoma cancer cell lines, both in vitro and in vivo [10][11][12], and our recent preliminary data suggest a potential therapeutic role for GLPG1790 also in treating CRC [13]. e present study has investigated the therapeutic efficiency of GLPG1790 against HCT116 and HCT15 CRC cell lines, both expressing a mutated form of KRAS in addition to either a wild-type p53 protein (p53 WT ) or mutated p53 (p53 MT ), respectively [14].…”

Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization

“…Target genes were analyzed by quantitative real-time PCR (qPCR), by using the following primers from Qiagen: SOD-2 (QT01008693), CAT (QT00079674), GPx4 (QT00067165), NRF2 (QT00027384) and β-Actin (ACTB) (QT00095431). Each sample was run in triplicate, in at least two independent experiments, on a StepOne Real Time System (Applied Biosystems) machine [15]. Relative quantification (RQ) of each mRNA in RR samples in comparison to PR-cells was calculated by the comparative Ct method (2 -ΔΔCt ), using the StepOne v2.3 software (Applied Biosystems).…”