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IFG signaling pathway

Tuesday 20 December 2011

The insulin-like growth factor (IGF) axis plays a pivotal role in regulating tumor cell growth, differentiation, tumor angiogenesis, metastasis, apoptosis, and MDR.

The IGF axis is composed of ligands, receptors, and IGF-binding proteins.

The balance between expression and activity of these molecules is tightly controlled under normal physiologic conditions; changes in this balance can cause numerous molecular events that can ultimately lead to malignancy.

Increased IGF-1 receptor (IGF-1R) and circulating IGF-1 expression is associated with an elevated risk for numerous cancer types and rapid disease progression, including HNSCC and NSCLC.

Increased bioactive IGF-II levels also result from reduced expression of IGF-binding protein or inactivation of the type 2 IGF receptor that mediates IGF-II degradation.

These changes can result in high local IGF tissue concentrations. In addition, the binding of IGFs to IGF-IR initiates conformational changes, transmembrane receptor tyrosine kinase (RTK) autophosphorylation, and Ras-Raf-mitogen–activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT signaling cascade activation, leading to the phosphorylation of several downstream substrates that are involved in cell proliferation, survival and apoptosis, inflammation, genomic instability, and angiogenesis.

Thus, IGF-1R signaling has been considered as a promising target for cancer therapy. Indeed, IGF-1R inactivation by gene disruption, antisense oligonucleotides, neutralizing antibodies, dominant-negative mutants, small molecule IGF-IR kinase inhibitors, and IGF-binding proteins has resulted in antitumor activity.

However, several clinical trials with anti–IGF-1R monoclonal antibodies (mAb) have shown modest therapeutic efficacy in clinical trials, and the mechanisms involved in resistance to the drug have not been clearly defined.

In a previous study, IGF and epidermal growth factor (EGF) stimulation both resulted in a physical association between the two receptors in a TU159 HNSCC cell line protein complex.

There are cross-talk between RTKs of EGF receptor (EGFR) and IGF receptor, wherein a inhibition of tyrosine kinase inhibitor (TKI) of one RTK is compensated by enhanced activity of the reciprocal RTK; thus, one suspected IGF-1R resistance mechanism is cross-talk with EGFR or other kinase receptors.

However, the involvement of the EGFR pathway in resistance to IGF-1R mAb-based anticancer therapy has not been defined. In this article, we report that inhibition of the IGF-1R pathway by cixutumumab (IMC-A12), a fully humanized IgG1 mAb, results in stimulation of the Akt/mTOR pathway through increasing synthesis of EGFR, Akt1, and antiapoptotic survivin proteins.

In addition, suppression of mTOR-mediated protein synthesis or inactivation of EGFR renders cixutumumab-resistant cells sensitive to the drug.

These results present a drug resistance mechanism of an IGF-1R–targeted agent as well as molecular targets to restore its antitumor activity.

Targeted therapy

Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb), but the resistance mechanisms have not been completely identified.

The cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual receptor tyrosine kinases.

For example, most head and neck squamous cell carcinoma (HNSCC) tissues had coexpression of total and phosphorylated IGF-1R and EGFR at high levels compared with paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mTOR, resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non–small cell lung cancer (NSCLC) cells. (Mol Cancer Ther; 10(12); 2437–48, 2011)

Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. Resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC. (Mol Cancer Ther; 10(12); 2437–48, 2011)

See also

- IGF signaling pathway