NVP-AEW541, a specific
ATP-competitive inhibitor of the
insulin-like growth factor-1 receptor (IGF1R)
tyrosine kinase, has been reported to interfere with
tumor growth in various
tumor transplantation models. We have assessed the efficacy of
NVP-AEW541 in repressing
tumor growth and
tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic β-cell
carcinogenesis. In addition, we have tested
NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated
tumor growth and increased
tumor malignancy compared with Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of
IGF-2, a high-affinity
ligand for IGF1R, are required for Rip1Tag2
tumor cell survival and
tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with
NVP-AEW541 in prevention and intervention trials neither did affect
tumor growth nor
tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to
tumor malignancy, that is, the rate of the transition from differentiated
adenoma to invasive
carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced
tumor volumes and increased rates of
tumor cell apoptosis. Sustained expression of
IGF-2 and of the IGF-2-binding form of
insulin receptor (IR-A) in
tumor cells suggests a compensatory role of IR-A upon IGF1R blockade. The results indicate that inhibition of IGF1R alone is not sufficient to efficiently block
insulinoma growth and imply an overlapping role of IGF1R and
insulin receptor in executing mitogenic and survival stimuli elicited by
IGF-2. The reduction of
tumor invasion upon IGF1R blockade on the other hand indicates a critical function of IGF1R signaling for the acquisition of a malignant phenotype.