Inhibition of the Insulin-like Growth Factor-1 Receptor (IGF1R) Tyrosine Kinase as a Novel Cancer Therapy Approach

Li, Rongshi; Pourpak, Alan; Morris, Stephan W.

doi:10.1021/jm9002395

Cited by 126 publications

(93 citation statements)

References 292 publications

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“…Combined, these results raise the intriguing possibility that miR-223* plays a cooperative role with miR-223 by targeting the same transcript within the IGF1R/PI3K axis, a key pathway for developmental and malignant processes. 36,37 miR-223* levels correlate with prognostic markers in AML patients…”

Section: Mir-223* and Mir-223 Target The Igf1r Pathwaymentioning

confidence: 99%

Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells

Kuchenbauer

Mah

Heuser

et al. 2011

Blood

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Section: Mir-223* and Mir-223 Target The Igf1r Pathwaymentioning

confidence: 99%

Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells

Kuchenbauer

Mah

Heuser

et al. 2011

Blood

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“…Furthermore, a growing body of evidence points out that IGF1R is essential for oncogenic transformation and is responsible for critical process of the metastatic cascade such as angiogenesis, cell adhesion, migration, and invasion [30,31]. Additionally, IGF1R has been regarded as a valuable therapeutic target, and IGF1R-antagonistic monoclonal antibodies have been raised against the activity of IGF1R [32]. Several miRNAs, such as miR-133, miR-143, miR-145, and miR-503 [33][34][35], have been shown the ability to target IGF1R gene expression in different tumors.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-182 suppresses clear cell renal cell carcinoma migration and invasion by targeting IGF1R

Wang¹,

H²,

L³

et al. 2016

neo

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The purpose of our study was aimed to determine the functional role of microRNA (miR)-182 in clear cell renal cell carcinoma (ccRCC) and try to clarify its underlying molecular mechanism. Expression of miR-182 in both cancer and peripheral blood samples was analyzed by quantitative real-time PCR (qRT-PCR). Human RCC line Caki-1 cells were transfected with miR-182 mimic, miR-182 inhibitor, or negative controls, and then the cell viability, colony-formation ability, migration, and invasion assay were determined. Luciferase reporter assay, qRT-PCR and Western blotting were used to determine whether insulin-like growth factor 1 receptor (IGF1R) was a target of miR-182. Further, small interfering RNA (siRNA) against IGF1R was co-transfected with miR-182 inhibitor into cells, and then the effects on migration and invasion were assessed. MiR-182 was down-regulated in both cancer and blood samples compared to the matched non-tumor adjacent tissues and healthy volunteers, respectively (both P<0.05). Compared to the control group, cell viability, colony-forming ability, and numbers of migrated and invaded cells were significantly decreased by transfection with miR-182 mimic but were markedly increased by miR-182 inhibitor (all P < 0.05). Luciferase reporter assay confirmed that IGF1R was a target gene of miR-182, and IGF1R was negatively regulated by miR-182. Co-transfection of miR-182 inhibitor with si-IGF1R reversed the effect of miR-182 inhibitor on the migration and invasion of the cells. MiR-182 functions as an anti-oncogene in ccRCC, and miR-182-mediated inhibition of cell migration and invasion might be through directly targeting IGF1R. Key words: MicroRNA-182, clear cell renal cell carcinoma, migration and invasion, insulin-like growth factor 1 receptorRenal cell carcinoma (RCC) is the most common malignant tumor of adult kidney and accounts for approximately 3% of adult cancers with a high mortality at over 40% [1,2]. Clear cell renal cell carcinoma (ccRCC) is the most frequent subtype of RCC accounting for about 75-80% of the tumor [3]. Despite a tremendous advance has been made in available treatments, the prognosis still remains dismal for locally advanced and metastatic RCC [4]. It has been reported that up to 30-40% of patients with RCC present with metastatic disease even after radical resections [5]. Therefore, it is necessary to provide knowledge of molecule mechanisms controlling the metastatic and invasive potential of RCC.MicroRNAs (miRNAs) are a class of small and non-coding RNA molecules that regulate mRNA transcription and translation by base pairing with the 3' untranslated region (UTR) [6]. It has been well demonstrated that miRNAs are involved in the development and progression of various cancers by regulating cell proliferation, invasion, and migration [7,8]. Recently, emerging evidence has suggested the significant roles of miRNAs in RCC [9][10][11]. Among miRNAs, miR-182 was recently found to be associated with the invasive and/or metastatic potential of prostate cancer [12], melanoma [13], an...

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“…The role of the insulin-like growth factor 1 receptor (IGF1R) in the pathogenesis of malignant epithelial tumours, including non-small cell lung cancer (NSCLC), has been well-characterised (1)(2)(3)(4)(5). Activation of this receptor pathway promotes tumour growth by inhibition of apoptosis, transformation, metastasis and induction of angiogenesis through vascular endothelial growth factor (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of the insulin-like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

Gately

Forde

Gray

et al. 2015

Molecular and Clinical Oncology

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Abstract. The insulin-like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well-documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single-nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16-21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease-free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P= 0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients. IntroductionThe role of the insulin-like growth factor 1 receptor (IGF1R) in the pathogenesis of malignant epithelial tumours, including non-small cell lung cancer (NSCLC), has been well-characterised (1-5). Activation of this receptor pathway promotes tumour growth by inhibition of apoptosis, transformation, metastasis and induction of angiogenesis through vascular endothelial growth factor (6-10).IGF1R is frequently overexpressed in NSCLC patients, however, there is controversy over its significance as a prognostic marker. Certain studies have shown no correlation between high IGF1R expression and patient survival (3,4); conversely, other studies have demonstrated that high IGF1R expression was associated with nodal metastasis, recurrence and a significantly poorer overall survival (OS) rate in NSCLC patients (11,12). A recent meta-analysis suggests IGF1R positive expression as an adverse factor for disease-free survival (DFS) in NSCLC pat...

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Inhibition of the Insulin-like Growth Factor-1 Receptor (IGF1R) Tyrosine Kinase as a Novel Cancer Therapy Approach

Cited by 126 publications

References 292 publications

Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells

Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells

MicroRNA-182 suppresses clear cell renal cell carcinoma migration and invasion by targeting IGF1R

Mutational analysis of the insulin-like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

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