Specific inhibition of the IGFR tyrosine kinase as a novel approach for targeted therapy in neuroendocrine gastrointestinal tumor disease

Background & Aims: Gastrointestinal neuroendocrine tumors (NET) represent a heterogeneous tumor entity. The antineoplastic treatment options of advanced neuroendocrine cancer disease are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. As NET cells frequently express insulin-like growth factors and their receptors (IGFR) which are known to promote survival, oncogenic transformation and tumor growth and spread, the IGF/IGFR system qualifies for novel targeted treatment approaches in NET disease. Here, we studied the antineoplastic effects of an inhibition of IGF–1 receptor (IGF–1R) signaling in NET cells by a novel IGF–1R tyrosine kinase (TK) inhibitor.

Methods & Results: Using the NET cell lines BON (human pancreatic carcinoid) and CM (human insulinoma) we could demonstrate that IGF–1R TK inhibition dose-dependently decreased the proliferation of NET cells by induction of apoptosis and cell cycle arrest. Apoptosis was characterized by activation of the apoptotic key enzyme caspase–3 as well as by detection of changes in the expression pattern of pro- and antiapoptotic proteins. Cell cycle was arrested at the G1/S checkpoint. The antineoplastic effects of IGF–1R TK inhibition involved the inactivation of mitogenic ERK1/2 signaling. Induction of immediate cytotoxicity did not account for the antineoplastic effects, as shown by measurement of LDH release. To translate the data obtained in cell lines to a more clinical model, primary cell cultures of resected human neuroendocrine gastrointestinal tumors were established and studied. Upon IGFR-TK inhibition strong antineoplastic effects of IGF–1R TK inhibition were also detected in primary cell cultures of intestinal NETs. Moreover, additive antineoplastic effects were observed when IGF–1R-TK inhibition was combined with cytostatics such as doxorubicin.

Conclusion: This is the first report on the induction of apoptosis and cell cycle arrest by IGF–1R TK inhibition in NET cells. The observed antineoplastic potency of IGFR-blockade indicates that inhibition of the IGF/IGFR system is a promising novel approach for future clinical trials in gastrointestinal NET disease.

Keywords: IGF receptor, antineoplastic, gastrointestinal neuroendocrine tumors, tyrosine kinase inhibitor