A novel approach in the treatment of neuroendocrine gastrointestinal tumors: targeting the epidermal growth factor receptor (EGFR) by gefitinib (ZD1839; Iressa)

Therapeutic options to inhibit growth and further spread of metastatic NE tumor disease are still limited. Here, we demonstrate that targeting the EGFR-sensitive tyrosine kinase (TK) by the EGFR-TK inhibitor gefitinib may be a promising future approach for effective growth control of NE tumors. mRNA- and protein expression of EGFR and EGFR-transactivating insulin-like growth factor receptors of three NE tumor cell lines with different growth characteristics was monitored by RT-PCR and flow-cytometry. In either cell line gefitinib induced a time- and dose-dependent growth inhibition by almost 100%. The antiproliferative potency of gefitinib correlated with the proliferation rate of the tumor cells: The IC₅₀ value of gefitinib was 4.7±0.6µM in the fast-growing human insulinoma CM cells, still 16.8±0.4µM in the moderate-growing human pancreatic carcinoid BON cells but up to 31.5±2.5µM in the slow-growing intestinal STC–1 NE tumor cells. Similarly, the induction of apoptosis and cell cycle arrest by gefitinib differed according to growth characteristics: Fast-growing CM cells displayed a strong G0/G1 arrest, while no significant cell cycle alterations were seen in the slow-growing STC–1. On the other hand, proapoptotic effects of gefitinib (caspase–3, DNA fragmentation) were most pronounced in the slow-growing STC–1 cells. cDNA microarrays revealed extensive changes in the expression pattern of apoptosis- and cell cycle-related genes after gefitinib treatment. Among them, a gefitinib-induced upregulation of the proapoptotic and cell cycle arresting GADD153 gene was observed. Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner. Interestingly, no gefitinib-induced activation of the GADD153 inducing p38 MAPK was detected. Furthermore, proapoptotic genes like BAD and caspase 4 were found to be up-regulated, while antiapoptotic genes were suppressed. Our data demonstrate that the inhibition of EGFR-TK by gefitinib induces growth inhibition, apoptosis and cell cycle arrest in neuroendocrine gastrointestinal tumor cells. Thus, EGFR-TK inhibition is a promising novel approach for the treatment of metastatic neuroendocrine tumor disease.

Key words

EGFR; Apoptose; Tyrosinkinase; neuroendokrine Tumoren