Targeting EGFR and IGF 1R a promising combination therapy for metastatic cancer

Singh, Inderpal

doi:10.2741/s369

Cited by 18 publications

(13 citation statements)

References 111 publications

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“…IGF-1R, a tyrosine kinase receptor, contains two extracellular α subunits with a ligand-binding site, two transmembrane β subunits and intracellular tyrosine kinase activity (29). It has previously been demonstrated that IGF-1R is involved in IGF-I and IGF-II signaling, and therefore regulates cell proliferation, cell cycle, apoptosis, metastasis, survival and differentiation (30)(31)(32)(33). IGF-1R has been investigated widely in glioma.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-186 targets IGF-1R and exerts tumor-suppressing functions in glioma

Jiang

Wang

Fang

et al. 2017

Molecular Medicine Reports

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Glioma is the most common malignant brain tumor in adults and represents one of the most aggressive and life‑threatening types of cancer in humans. Increasing studies have revealed that microRNAs are abnormally expressed in various types of human cancer, and have oncogenic or tumor suppressive roles, which depend primarily on the type of cancer. The present study aimed to investigate the expression level and effects of microRNA‑186 (miR‑186) on glioma, and its underlying molecular mechanism. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis was performed to detect the expression of miR‑186 in glioma tissues and cell lines. Cell proliferation and invasion were assessed using MTT and cell invasion assays, respectively. Bioinformatics analysis and a luciferase reporter assay were performed to identify insulin‑like growth factor 1 receptor (IGF‑1R) as a novel target gene of miR‑186. The mRNA expression level of IGF‑1R was also measured using RT‑qPCR analysis. The association between miR‑186 and the expression of IGF‑1R was evaluated using Spearman's correlation anal-ysis. Furthermore, the regulatory effects of miR‑186 on the mRNA and protein expression of IGF‑1R were determined using RT‑qPCR and western blot analyses. Finally, the biological effects of the underexpression IGF‑1R on glioma cells were investigated. The results showed that miR‑186 was significantly downregulated in glioma tissues and cell lines. Inducing the expression of miR‑186 suppressed glioma cell proliferation and invasion. IGF‑1R was confirmed as a direct target gene of miR‑186. In addition, the mRNA expression of IGF‑1R was upregulated and inversely correlated with that of miR‑186 in glioma tissues. The effects of IGF‑1R‑knockdown on glioma cell proliferation and invasion were similar to the effects induced by the overexpression of miR‑186. These findings demonstrated that miR‑186 acted as a tumor suppressor by targeting IGF‑1R in glioma, suggesting miR‑186 may be a potential therapeutic target for the treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-186 targets IGF-1R and exerts tumor-suppressing functions in glioma

Jiang

Wang

Fang

et al. 2017

Molecular Medicine Reports

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“…Furthermore, a phase II study of anti-IGF1R mAb MK-0646 in combination with anti-EGFR mAb cetuximab and irinotecan has been reported to be effective and tolerable [35]. Additionally, it has been reported that this combinational regimen would be well tolerated owning to lack of duplicate toxicities between inhibitors of IGF1R and EGFR [36]. However, at this point, no studies have examined the role of co-inhibition of EGFR and IGF1R in the treatment of ACC.…”

Section: Discussionmentioning

confidence: 99%

Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma

et al. 2016

Oncotarget

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PurposeAdrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo.MethodsThe expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed.ResultsOur results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs (P<0.05). Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively. Meanwhile, we found that single inhibition of IGF1R induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of EGFR and IGF1R downstream components. More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo.ConclusionsIn conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future.

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“…We also identified that miR-133a can downregulate multiple targets and that these targets are all oncogenic membrane receptors, namely EGFR, IGF-1R, and TGFBR1 (Figure 5D). The oncogenic roles of these receptors have been well identified, and they are all important therapeutic targets or molecular markers for cancer treatment [30], [31].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-133a Suppresses Multiple Oncogenic Membrane Receptors and Cell Invasion in Non-Small Cell Lung Carcinoma

et al. 2014

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Non-small cell lung cancers (NSCLCs) cause high mortality worldwide, and the cancer progression can be activated by several genetic events causing receptor dysregulation, including mutation or amplification. MicroRNAs are a group of small non-coding RNA molecules that function in gene silencing and have emerged as the fine-tuning regulators during cancer progression. MiR-133a is known as a key regulator in skeletal and cardiac myogenesis, and it acts as a tumor suppressor in various cancers. This study demonstrates that miR-133a expression negatively correlates with cell invasiveness in both transformed normal bronchial epithelial cells and lung cancer cell lines. The oncogenic receptors in lung cancer cells, including insulin-like growth factor 1 receptor (IGF-1R), TGF-beta receptor type-1 (TGFBR1), and epidermal growth factor receptor (EGFR), are direct targets of miR-133a. MiR-133a can inhibit cell invasiveness and cell growth through suppressing the expressions of IGF-1R, TGFBR1 and EGFR, which then influences the downstream signaling in lung cancer cell lines. The cell invasive ability is suppressed in IGF-1R- and TGFBR1-repressed cells and this phenomenon is mediated through AKT signaling in highly invasive cell lines. In addition, by using the in vivo animal model, we find that ectopically-expressing miR-133a dramatically suppresses the metastatic ability of lung cancer cells. Accordingly, patients with NSCLCs who have higher expression levels of miR-133a have longer survival rates compared with those who have lower miR-133a expression levels. In summary, we identified the tumor suppressor role of miR-133a in lung cancer outcome prognosis, and we demonstrated that it targets several membrane receptors, which generally produce an activating signaling network during the progression of lung cancer.

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Targeting EGFR and IGF 1R a promising combination therapy for metastatic cancer

Cited by 18 publications

References 111 publications

MicroRNA-186 targets IGF-1R and exerts tumor-suppressing functions in glioma

MicroRNA-186 targets IGF-1R and exerts tumor-suppressing functions in glioma

Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma

MicroRNA-133a Suppresses Multiple Oncogenic Membrane Receptors and Cell Invasion in Non-Small Cell Lung Carcinoma

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