Impact of IGF‐1R/EGFR cross‐talks on hepatoma cell sensitivity to gefitinib

Desbois-Mouthon, Christèle; Cacheux, Wulfran; Eggelpoël, Marie-José Blivet-Van; Barbu, Véronique; Fartoux, Lætitia; Poupon, Raoul; Housset, Chantal; Rosmorduc, Olivier

doi:10.1002/ijc.22221

Cited by 109 publications

(82 citation statements)

References 53 publications

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“…Equally, IGF-Ⅱ induced tumor cell motility was reduced by picropodophyllin (Nussbaum et al, unpublished data). In addition, the inhibition of IGF-IR-signaling by a combination of AG1024 and EGF-R-signaling by RTKinhibitors or blocking antibodies synergistically reduced tumor growth [114,115] . However, NVP-ADW742 affects the viability of hepatocytes in a concentration-dependent manner.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Breuhahn¹

2008

WJG

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Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Breuhahn¹

2008

WJG

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“…Combinations of IGF-1R and EGFR inhibitory antibodies have also shown improved activity in A549 xenografts relative to individual agents (26). In addition, a nonselective IGF-1R kinase inhibitor, AG1024, enhanced the ability of gefitinib or erlotinib to block proliferation and induce apoptosis of breast cancer (27), hepatoma (28), and NSCLC cell lines (20,24).…”

Section: Igf-1rmentioning

confidence: 99%

Insulin-like Growth Factor-1 Receptor and ErbB Kinase Inhibitor Combinations Block Proliferation and Induce Apoptosis through Cyclin D1 Reduction and Bax Activation

Wilsbacher

Zhang

Tucker

et al. 2008

Journal of Biological Chemistry

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The insulin-like growth factor-1 receptor (IGF-1R) and ErbB family of receptors are receptor tyrosine kinases that play important roles in cancer. Lack of response and resistance to therapies targeting ErbB receptors occur and are often associated with activation of the IGF-1R pathway. Combinations of agents that inhibit IGF-1R and ErbB receptors have been shown to synergistically block cancer cell proliferation and xenograft tumor growth. To determine the mechanism by which targeting both IGF-1R and ErbB receptors causes synergistic effects on cell growth and survival, we investigated the effects of combinations of selective IGF-1R and ErbB kinase inhibitors on proliferative and apoptotic signaling. We identified A431 squamous cell carcinoma cells as most sensitive to combinations of ErbB and IGF-1R inhibitors. The inhibitor combinations resulted in not only blockade of A431 cell proliferation, but also induced apoptosis, which was not seen with either agent alone. Upon examining phosphorylation states and expression levels of proteins in the IGF-1R and ErbB signaling pathways, we found a correlation between the ability of combinations to inhibit proliferation and to decrease levels of phosphorylated Akt and cyclin D1. In addition, the massive cell death induced by combined IGF-1R/ErbB inhibition was associated with Mcl-1 reduction and Bax activation. Thus, targeting both IGF-1R and ErbB receptors simultaneously results in cell cycle arrest and apoptosis through combined effects on Akt, cyclin D1, and Bax activation. IGF-1R2 function is important for cellular processes that are activated in cancer cells, including cell proliferation, survival, metastasis, and invasion (1-4). Transformation of cells by several oncogenes has been shown to require IGF-1R function (2, 5), and anchorage-independent growth (3) and survival of cancer cells in response to cellular stress (5) can both be mediated by the IGF-1R. IGF-1R stimulates cell proliferation and survival through activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and Akt pathways. Upon binding of IGF-1 or IGF-2 to the IGF-1R, the receptor becomes autophosphorylated on several tyrosine residues. These phosphotyrosines serve as binding sites for adaptor proteins, including insulin receptor substrate (IRS)-1-4 and Shc, which are then phosphorylated by the activated receptor. Phosphorylated IRS and Shc in turn recruit Grb2/SOS, which leads to activation of the MAPK pathway, and the p85 subunit of phosphatidylinositol 3-kinase, resulting in phosphatidylinositol 3,4,5-trisphosphate production and Akt activation (3, 6, 7). The MAPK and Akt pathways regulate levels of cell cycle proteins like cyclin D1 and p27 to cause increased cell proliferation (8) and decrease apoptosis by phosphorylating the proapoptotic protein, Bad, which results in its sequestration by 14-3-3 (9). Antibodies that target IGF-1R and one small molecule IGF-1R inhibitor are undergoing clinical trials, and several other IGF-1R small molecule inhibitors ...

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“…IGF-II promotes proliferation, survival, and migration in hepatoma cells through binding to its receptor IGF type 1 receptor (IGF-1R; refs. [8][9][10]. This receptor as well as its main substrates IRS-1 and IRS-2 may be also overexpressed in HCC and in experimental models of liver carcinogenesis (11)(12)(13)(14).…”

mentioning

confidence: 99%

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

Desbois-Mouthon

Baron

Eggelpoël

et al. 2009

Clinical Cancer Research

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110

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Purpose: The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor. Experimental Design: Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti-IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines. Results: Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642. Conclusions: These findings indicate that hepatoma cells overcome IGF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC]. (Clin Cancer Res 2009;15(17):5445-56)

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Impact of IGF‐1R/EGFR cross‐talks on hepatoma cell sensitivity to gefitinib

Cited by 109 publications

References 53 publications

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

Insulin-like Growth Factor-1 Receptor and ErbB Kinase Inhibitor Combinations Block Proliferation and Induce Apoptosis through Cyclin D1 Reduction and Bax Activation

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

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