The Insulin Receptor/Insulin-Like Growth Factor Receptor Family as a Therapeutic Target in Oncology

Pollak, Michael

doi:10.1158/1078-0432.ccr-11-0998

Cited by 88 publications

(89 citation statements)

References 81 publications

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“…Also, IR has been shown to form hetero-receptor complexes with IGF receptor, which could be activated by other insulin-like growth factors as well. 44 Taken together, our results suggest a direct negative regulation of PTEN by insulin and IR. Although this is certainly not the sole mechanism that accounts for the higher cancer risk found in hyperinsulinemia or IR overexpressing individuals, our model provides a promising foothold that cancer biologists should consider when designing drugs for targeted cancer therapy.…”

Section: Discussionsupporting

confidence: 54%

Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

et al. 2013

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Insulin and insulin-like growth factor-1 signaling have fundamental roles in energy metabolism, growth and development. Recent research suggests hyperactive insulin receptor (IR) and hyperinsulinemia are cancer risk factors. However, the mechanisms that account for the link between the hyperactive insulin signaling and cancer risk are not well understood. Here we show that an insulin-like signaling inhibits the DAF-18/(phosphatase and tensin homolog) PTEN tumour suppressor in Caenorhabditis elegans and that this regulation is conserved in human breast cancer cells. We show that inhibiting the IR increases PTEN protein levels, while increasing insulin signaling decreases PTEN protein levels. Our results show that the kinase region of IRb subunit physically binds to PTEN and phosphorylates on Y27 and Y174. Our genetic results also show that DAF-2/IR negatively regulates DAF-18/PTEN during C. elegans axon guidance. As PTEN is an important tumour suppressor, our results therefore suggest a possible mechanism for increased cancer risk observed in hyperinsulinemia and hyperactive IR individuals.

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Section: Discussionsupporting

confidence: 54%

Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

et al. 2013

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“…As attempts of targeting cancer development by blocking IGFBP-2 activity [35][36][37] or ezrin phosphorylation 18 are already ongoing, we anticipate that further elucidation of the detailed molecular pathways by which L1 mediates human CRC metastasis will bring us closer to achieving this aim.…”

Section: Discussionmentioning

confidence: 99%

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

et al. 2012

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1L1, a neuronal cell adhesion receptor of the immunoglobulin-like protein family is expressed in invading colorectal cancer (CRC) cells as a target gene of Wnt/b-catenin signaling. Overexpression of L1 in CRC cells enhances cell motility and proliferation, and confers liver metastasis. We recently identified ezrin and the IkB-NF-kB pathway as essential for the biological properties conferred by L1 in CRC cells. Here, we studied the underlying molecular mechanisms and found that L1 enhances ezrin phosphorylation, via Rho-associated protein kinase (ROCK), and is required for L1-ezrin co-localization at the juxtamembrane domain and for enhancing cell motility. Global transcriptomes from L1-expressing CRC cells were compared with transcriptomes from the same cells expressing small hairpin RNA (shRNA) to ezrin. Among the genes whose expression was elevated by L1 and ezrin we identified insulin-like growth factor-binding protein 2 (IGFBP-2) and showed that its increased expression is mediated by an NF-kB-mediated transactivation of the IGFBP-2 gene promoter. Expression of a constitutively activated mutant ezrin (Ezrin567D) could also increase IGFBP-2 levels in CRC cells. Overexpression of IGFBP-2 in CRC cells lacking L1-enhanced cell proliferation (in the absence of serum), cell motility, tumorigenesis and induced liver metastasis, similar to L1 overexpression. Suppression of endogenous IGFBP-2 in L1-transfected cells inhibited these properties conferred by L1. We detected IGFBP-2 in a unique organization at the bottom of human colonic crypts in normal mucosa and at increased levels throughout human CRC tissue samples co-localizing with the phosphorylated p65 subunit of NF-kB. Finally, we found that IGFBP-2 and L1 can form a molecular complex suggesting that L1-mediated signaling by the L1-ezrin-NF-kB pathway, that induces IGFBP-2 expression, has an important role in CRC progression.Oncogene ( In recent studies, we identified members of the immunoglobulin-like cell adhesion receptors (Nr-CAM and L1), mostly known for their function in nerve cells, 3,4 but also in many cancer cell types, 5 as target genes of b-catenin-TCF signaling in CRC cells. 6,7 We detected L1 in a subpopulation of cells at the invasive front of CRC tissue displaying nuclear b-catenin localization. 7 We further found that the expression of L1 in human CRC cells, lacking endogenous L1, confers enhanced motility and metastasis to the liver in a mouse metastasis model.

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“…Therapeutics aimed at inhibiting IGF-I receptor IGF-IR signaling, a key prosurvival pathway that activates the PI3K/AKT/mTOR cascade, were first envisioned as mechanisms to overcome resistance (11)(12)(13). Preclinical evidence supports a role for IGF-IR in reducing the effectiveness of anti-ErbB2 and anti-EGFR therapies, requiring coblockade of the PI3K/AKT/mTOR cascade (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

Fitzgerald

Johnson

Baum

et al. 2014

Molecular Cancer Therapeutics

102

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Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR-mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410-25. Ó2013 AACR.

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The Insulin Receptor/Insulin-Like Growth Factor Receptor Family as a Therapeutic Target in Oncology

Cited by 88 publications

References 81 publications

Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

Insulin activates the insulin receptor to downregulate the PTEN tumour suppressor

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

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