The insulin-like growth factor receptor is a promising target for innovative treatment approaches of hepatocellular cancer

Background & Aims: Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. Due to very poor 5-year-survival new therapeutic approaches are uregently needed. Most HCCs express insulin-like growth factors and their receptors (IGFR). As IGF–1R-mediated signaling promotes survival, oncogenic transformation and tumor growth and spread, it represents a potential target for innovative treatment strategies of HCC. Here we studied the effects of a novel IGF–1R tyrosine kinase inhibitor in human HCC cells and focused on the antineoplastic efficacy of IGF-receptor inhibition alone as well as in combination with other growth factor receptor agents or cytostatics.

Methods & Results: The orally available low molecular weight IGF–1R tyrosine kinase inhibitor NVP-AEW541 induced a time- and dose-dependent growth inhibition in human HCC cell line models. Measurement of LDH-release showed that the antineoplastic effect of NVP-AEW541 was not due to cytotoxicity. Instead NVP-AEW541 induced apoptosis as evidenced by both caspase–3 and –8 activation as well as by morphological and mitochondrial apoptosis-specific changes. In addition, nuclear degradation was monitored by DNA-laddering. NVP-AEW541-treatment suppressed the expression of the antiapoptotic proteins Bcl–2 and survivin, while the expression of the proapoptotic protein BAX was stimulated in a dose-dependent manner. Additonally, NVP-AEW541 arrested the cell cycle at the G1/S checkpoint. When NVP-AEW541 was combined with specific antibodies directed against either the epidermal growth factor receptor (EGFR) or the IGF–1R, additive antiproliferative effects were observed. Enhanced antiproliferative effects were also observed, when NVP-AEW541 was combined with either doxorubicin or docetaxel.

Conclusion: Inhibition of IGF–1R tyrosine kinase (TK) activity induces growth inhibition, apoptosis and cell cycle arrest in human HCC cells without being cytotoxic. Moreover, IGF–1R-TK inhibition appears to be particularly promising for combined treatment strategies, including cytostatics and other blockers of growth factor receptor signaling. Especially, combined inhibition of EGFR- and IGFR-signaling appears to be a promising strategy to be tested in future clinical trials in HCC disease.

Keywords: IGF receptor, apoptosis, hepatocellular cancer, targeted therapy, tyrosine kinase