Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies.
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ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC8193947 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundReceptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart.MethodsRTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays.ResultsIn addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation.ConclusionsSeveral novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.
| S-EPMC6196006 | biostudies-literature
Project description:Receptor tyrosine kinases (RTKs) have provided molecular targets for the development of novel, prognosis-improving agents in many cancers; however, resistances to these therapies occur. On the cellular level, one resistance mechanism is attributed to functional RTK redundancies and compensatory cross-signaling, leading to perception of RTKs as signaling and target networks. To provide a basis for better exploitation of this network in Ewing sarcoma, we generated comprehensive qPCR gene expression profiles of RTKs in Ewing sarcoma cell lines and 21 untreated primary tumors. Key findings confirm broad-spectrum RTK expressions with potential for signaling redundancy. Profile analyses with regard to patient risk-group further revealed several individual RTKs of interest. Among them, VEGFR3 and TIE1 showed high-level expressions and also were suggestive of poor prognosis in localized tumors; underscoring the relevance of angiogenic signaling pathways and tumor-stroma interactions in Ewing sarcoma. Of note, compared to localized disease, tumors derived from metastatic disease were marked by global high-level RTK expressions. Nine individual RTKs were significantly over-expressed, suggesting contributions to molecular mechanisms of metastasis. Of these, ROR1 is being pursued as therapeutic target in leukemias and carcinomas, but un-characterized in sarcomas. We demonstrate expression of ROR1 and its putative ligand Wnt5a in Ewing sarcomas, and of an active ROR1 protein variant in cell lines. ROR1 silencing impaired cell migration in vitro. Therefore, ROR1 calls for further evaluation as a therapeutic target in metastatic Ewing sarcoma; and described as a pseudo-kinase with several isoforms, underlines these additional complexities arising in our understanding of RTK signaling networks.
| S-EPMC5423155 | biostudies-literature
Project description:The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these-crizotinib, ceritinib, and alectinib-are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations.
| S-EPMC5171696 | biostudies-literature
Project description:Molecular therapeutics for treating epidermal growth factor receptor-(EGFR-) expressing cancers are a specific method for treating cancers compared to general cell loss with standard cytotoxic therapeutics. However, the finding that resistance to such therapy is common in clinical trials now dampens the initial enthusiasm over this targeted treatment. Yet an improved molecular understanding of other receptor tyrosine kinases known to be active in cancer has revealed a rich network of cross-talk between receptor pathways with a key finding of common downstream signaling pathways. Such cross talk may represent a key mechanism for resistance to EGFR-directed therapy. Here we review the interplay between EGFR and Met and the type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinases, as well as their contribution to anti-EGFR therapeutic resistance in the context of squamous cell cancer of the head and neck, a tumor known to be primarily driven by EGFR-related oncogenic signals.
| S-EPMC3135278 | biostudies-literature
Project description:Tyrosine kinase fusion genes represent an important class of oncogenes associated with leukaemia and solid tumours. They are produced by translocations and other chromosomal rearrangements of a subset of tyrosine kinase genes, including ABL, PDGFRA, PDGFRB, FGFR1, SYK, RET, JAK2 and ALK. Based on recent findings, this review discusses the common mechanisms of activation of these fusion genes. Enforced oligomerization and inactivation of inhibitory domains are the two key processes that switch on the kinase domain. Activated tyrosine kinase fusions then signal via an array of transduction cascades, which are largely shared. In addition, the fusion partner provides a scaffold for the recruitment of proteins that contribute to signalling, protein stability, cellular localization and oligomerization. The expression level of the fusion protein is another critical parameter. Its transcription is controlled by the partner gene promoter, while translation may be regulated by miRNA. Several mechanisms also prevent the degradation of the oncoprotein by proteasomes and lysosomes, leading to its accumulation in cells. The selective inhibition of the tyrosine kinase activity by adenosine-5'-triphosphate competitors, such as imatinib, is a major therapeutic success. Imatinib induces remission in leukaemia patients that are positive for BCR-ABL or PDGFR fusions. Recently, crizotinib produced promising results in a subtype of lung cancers with ALK fusion. However, resistance was reported in both cases, partially due to mutations. To tackle this problem, additional levels of therapeutic interventions are suggested by the complex mechanisms of fusion tyrosine kinase activation. New approaches include allosteric inhibition and interfering with oligomerization or chaperones.
| S-EPMC3823288 | biostudies-literature
Project description:In recent years, new classes of molecules have been established as opportunities for the treatment of breast cancer. The approval of trastuzumab, the antibody against Her2/neu, in the late 1990s was followed by the approval of the antiangiogenic antibody bevacizumab in 2007. Progress in the understanding of the molecular mechanisms of carcinogenesis and tumour growth led to the development of new molecules, mostly kinase inhibitors. A few of these new molecues gained approval in several countries; clinical trials aiming at further approvals are ongoing. This short review covers the actual state-of-the-art and possible future developments in the targeted therapy of breast cancer.
| S-EPMC2942015 | biostudies-other
Project description:Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.
| S-EPMC5362808 | biostudies-literature
Project description:Phosphorylation of receptor tyrosine kinases (RTKs) has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL). Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38) applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature) and glycosylated (mature) ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03). The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa) isoform was significantly higher in progressive than in non-progressive disease (p<0.001). Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.
| S-EPMC3813472 | biostudies-literature
Project description:Background and Objectives: Identification and targeting of membrane proteins in tumor cells is one of the key steps in the development of cancer drugs. The receptor tyrosine kinase-like orphan receptor (ROR) type 1 is a type-I transmembrane protein expressed in various cancer tissues, which is in contrast to its limited expression in normal tissues. These characteristics make ROR1 a candidate target for cancer treatment. This study aimed to identify the prognostic value of ROR1 expression in cancers. Materials and Methods: We conducted a comprehensive systematic search of electronic databases (PubMed) from their inception to September 2021. The included studies assessed the effect of ROR1 on overall survival (OS) and progression-free survival (PFS). Hazard ratios (HR) from collected data were pooled in a meta-analysis using Revman version 5.4 with generic inverse-variance and random effects modeling. Results: A total of fourteen studies were included in the final analysis. ROR1 was associated with worse OS (HR 1.95, 95% confidence interval (CI) 1.50−2.54; p < 0.001) with heterogeneity. The association between poor OS and ROR1 expression was high in endometrial cancer, followed by ovarian cancer, and diffuse large B cell lymphoma. In addition, ROR1 was associated with poor PFS (HR 1.84, 95% CI 1.60−2.10; p < 0.001), but heterogeneity was not statistically significant. In subgroup analysis, high ROR1 expression showed a significantly higher rate of advanced stage or lymph node metastasis. Conclusions: This meta-analysis provides evidence that ROR1 expression is associated with adverse outcome in cancer survival. This result highlights ROR1 as a target for developmental therapeutics in cancers.
| S-EPMC9784027 | biostudies-literature
Project description:We have previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a direct transcriptional target of TTF-1/NKX2-1, a lineage-survival oncogene in lung adenocarcinoma. ROR1 sustains prosurvival signaling from multiple receptor tyrosine kinases including epidermal growth factor receptor, MET, and insulin-like growth factor 1 receptor in part by maintaining the caveolae structure as a scaffold protein of cavin-1 and caveolin-1. In this study, a high throughput screening of the natural product library containing 2560 compounds was undertaken using a cell-based FluoPPI assay detecting ROR1-cavin-1 interaction. As a result, geldanamycin (GA), a known inhibitor of heat shock protein 90 (HSP90), was identified as a potential inhibitor of ROR1. Geldanamycin, as well as two GA derivatives tested in the clinic, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreased ROR1 protein expression. We found that ROR1 physically interacted with HSP90α, but not with other HSP90 paralogs, HSP90β or GRP94. Geldanamycin in turn destabilized and degraded ROR1 protein in a dose- and time-dependent manner through the ubiquitin/proteasome pathway, resulting in a significant suppression of cell proliferation in lung adenocarcinoma cell lines, for which the kinase domain of ROR1, but not its kinase activity or N-glycosylation, was required. Our findings indicate that HSP90 is required to sustain expression of ROR1 crucial for lung adenosarcoma survival, suggesting that inhibition of HSP90 could be a promising therapeutic strategy in ROR1-positive lung adenocarcinoma.
| S-EPMC7935804 | biostudies-literature