Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma

We determined whether down-regulation of the epidermal growth factor-recept or (EGF-R) signaling pathway by oral administration of a novel EGF-R tyrosi ne kinase inhibitor (PKI166) alone or in combination with gemcitabine (admi nistered i.p.) can inhibit growth and metastasis of human pancreatic carcin oma cells implanted into the pancreas of nude mice. Therapy beginning 7 day s after orthotopic injection of L3.6pl human pancreatic cancer cells reduce d the volume of pancreatic tumors by 59% in mice treated with gemcitabine o nly, by 45% in those treated with PKI166 only, and by 85% in those given bo th drugs. The combination therapy also significantly inhibited lymph node a nd liver metastasis, which led to a significant increase in overall surviva l, EGF-R activation was significantly blocked by therapy with PKI166 and wa s associated with significant reduction in tumor cell production of VEGF an d IL-8, which in turn correlated with a significant decrease in microvessel density and an increase in apoptotic endothelial cells. Collectively, our results demonstrate that oral administration of an EGF-R tyrosine kinase in hibitor decreased growth and metastasis of human pancreatic cancer growing orthotopically in nude mice and increased survival. The therapeutic effects were mediated in part by inhibition of tumor-induced angiogenesis attribut able to a decrease in production of proangiogenic molecules by tumor cells and increased apoptosis of tumor-associated endothelial cells.