Abstract
Erythropoietin-producing hepatocellular receptors (Eph) promote the onset and sustain the progression of cancers such as colorectal cancer (CRC), in which the A2 subtype of Eph receptor expression has been shown to correlate with a poor prognosis and has been identified as a promising therapeutic target. Herein, we investigated, in vitro and in vivo, the effects of treatment with GLPG1790, a potent pan-Eph inhibitor. The small molecule has selective activity against the EphA2 isoform in human HCT116 and HCT15 CRC cell lines expressing a constitutively active form of RAS concurrently with a wild-type or mutant form of p53, respectively. GLPG1790 reduced EPHA2 phosphorylation/activation and induced G1/S cell-cycle growth arrest by downregulating the expression of cyclin E and PCNA, while upregulating p21Waf1/Cip1 and p27Cip/Kip. The inhibition of ephrin signaling induced quiescence in HCT15 and senescence in HCT116 cells. While investigating the role of CRC-related, pro-oncogenic p53 and RAS pathways, we found that GLPG1790 upregulated p53 expression and that silencing p53 or inhibiting RAS (human rat sarcoma)/ERKs (extracellular signal-regulated kinase) signaling restrained the ability of GLPG1790 to induce senescence in HCT116 cells. On the other hand, HCT15 silencing of p53 predisposed cells to GLPG1790-induced senescence, whilst no effects of ERK inhibition were observed. Finally, GLPG1790 hindered the epithelial-mesenchymal transition, reduced the migratory capacities of CRC, and affected tumor formation in xenograft models in vivo more efficiently using HCT116 than HCT15 for xenografts. Taken together, our data suggest the therapeutic potential of GLPG1790 as a signal transduction-based therapeutic strategy in to treat CRC.
Highlights
Colorectal cancer (CRC) is the third and second most commonly occurring cancer in men and in women, respectively, with 1 million of new cases diagnosed every year [1]
E erythropoietin-producing hepatocellular carcinoma receptors (Eph) constitute the largest family of receptor tyrosine kinases (RTKs). e family comprised sixteen total receptors divided into either A- or B-subclasses. e EphA group consists of EphA1 to EphA10 receptors, and the EphB group comprised six receptors named EphB1 to EphB6
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 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 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 Kirsten rat sarcoma viral oncogene homolog (KRAS) in addition to either a wild-type p53 protein (p53WT) or mutated p53 (p53MT), respectively [14]
Summary
Colorectal cancer (CRC) is the third and second most commonly occurring cancer in men and in women, respectively, with 1 million of new cases diagnosed every year [1]. CRC develops through different stages and is promoted by the accumulation of acquired or inherited genetic mutations that eventually promote malignant evolution [2] In this regard, mutation of adenomatous polyposis coli (APC), Kirsten rat sarcoma viral oncogene homolog (KRAS), and tumor protein 53 (TP53 or p53) have been extensively investigated and have been shown to play a key role in the progression of CRC [3]. Eph regulates several biological processes through different kinase-mediated forward and reverse pathways that include small GTPases of Rho members, RAS, focal adhesion kinase (FAK), the PI3 kinase pathway (PI3K), the Jak/Stat pathway, and Src [4, 5] Because of their critical role in regulating several physiological processes, the aberrant expression of Ephs and ephrins has been reported in many human tumors including CRC [6, 7]. We found that the mutational status of p53, along with RAS (human rat sarcoma)/ERKs (extracellular signal-regulated kinase) signaling, affected GLPG1790-mediated anticancer activity that was higher in p53WT expressing cells. us, data collected here support the idea that targeting Eph may offer a new means of developing novel anticancer strategies against CRC
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